31 matching studies

Sponsor Condition of Interest
Clostridium perfringens enterotoxin and Rotaviral gastroenteritis as novel candidate triggers for Sudden...
Rockefeller University Sudden Infant Death Syndrome
Sudden Infant Death Syndrome (SIDS) is the leading cause of death in children less than one year of age (one death for every 1250 births). Surely the impact of SIDS on parents and families is tragic. However the cause of this disease remains unknown. Our current understanding of SIDS involves unexplained... expand

Sudden Infant Death Syndrome (SIDS) is the leading cause of death in children less than one year of age (one death for every 1250 births). Surely the impact of SIDS on parents and families is tragic. However the cause of this disease remains unknown. Our current understanding of SIDS involves unexplained abnormalities in the region of the brain that controls our automatic desire to breathe. In SIDS the nerve cells that comprise this brain region are decreased in number. Furthermore there is evidence of brain injury suggesting that some form of damage has previously occurred. Typically children who die from SIDS are laid down to sleep for the night and find themselves in sleeping positions that cause them to rebreathe spent air (e.g. face down). Without this automatic respiratory drive these infants fail to reposition themselves such that they can breathe fresh well-oxygenated air and they die of suffocation. The leading hypothesis for how SIDS related brain damage occurs is that there is a defect during brain development; however I will suggest that other mechanisms may be play. Bacteria release a substance called a toxin that causes damage to human cells. These bacterial toxins have also drawn attention in SIDS research. One toxin in particular made by the bacteria called Clostridium perfringens has been previously implicated. Interestingly researchers have found that Clostridium can be identified in the intestines of up to 81% children who died from SIDS compared to just 20% healthy infants. Furthermore damage to the intestine has been identified in 84% SIDS cases and can be recreated in an animal studies. Comparison of magnified images shows striking similarities between the intestinal damage present in children who died from SIDS and the intestinal damage found in experimental animals that have been exposed to toxin. How toxin may weaken the automatic desire to breathe in children who died from SIDS remains unknown. Data from our laboratory has identified that the cells responsible for our desire to breathe are susceptible to Clostridium toxin. Similarly our data also show that a virus called Rotavirus which causes infant diarrhea may also be involved. Briefly the brain cells involved in the automatic desire to breathe also express receptors for Rotavirus and one scientific study has shown evidence for Rotavirus infection in children who died from SIDS. These findings may explain how the brain damage in SIDS occurs. In light of our recent findings we wish to collect stool samples from healthy infants and compare them to children who died fromSIDS . We will assess and compare the presence of the Clostridium toxin and Rotavirus between SIDS and healthy infants. (Please note that frozen fecal samples from infants with SIDS were previously collected under the PIs protocol "Identification of Clostridium perfringens enterotoxin as a novel candidate trigger for SIDS" deemed as Not Human Subjects Research in Decemebr 2015.)

Type: Observational

open study

Biomarker assay development and quality control assays for studies of exRNA/extracellular nucleic acids.
Rockefeller University Healthy volunteers
Ribonucleic acid (RNA) is a biomolecule with a variety of function within living cells. It is biochemically very similar to deoxyribonucleic acid (DNA) the biomolecule encoding the genetic information. In contrast to DNA however RNA is less stable and easily degraded by ubiquitiously present enzymes... expand

Ribonucleic acid (RNA) is a biomolecule with a variety of function within living cells. It is biochemically very similar to deoxyribonucleic acid (DNA) the biomolecule encoding the genetic information. In contrast to DNA however RNA is less stable and easily degraded by ubiquitiously present enzymes (RNases or more generally nucleases). There is a high nuclease activity in extracellular fluids (biofluids) so that extracellular RNA are commonly viewed as being rapidly degraded and useless for diagnostic applications. But recent research inlcuding in our laboratory showed that at least certain RNA classes are to a certain degree protected from degradation. This is particularly true for miRNAs. We and others have shown that they can be reliably measured in the blood circulation and that a characteristic and robust miRNA signature exists for selected diseases or in pregnancy. However there is very limited data on the biogenesis or the clearance of RNA containing complexes circulating micro RNAs (miRNAs) and almost no data about confounding factors during the sample preparation. Our data on archived clinical samples and publications by other groups indicate that the extracellular RNA content is strongly influenced by blood cell damage variables during samples procurement sample handling as well as by different RNA isolation methods. The use of assays based on distinct technologies and the lack of standardization and precise quantification additionally makes it very hard to compare available results. In this study which follows our pilot study on exRNA isolation for biomarker discovery (IRB KAK-839) we want to identify confounders in sample handling and quantification that can critically influence the circulating RNA profile. In addition we aim to explore techniques for enrichment or concentration of certain RNA classes including but not limited to messenger RNAs (mRNAs) that can be linked to physiological and pathophysiological states. While our focus of this study is on RNA retrieval an characterization a second goal is to direct method development towards optionally extracting extracellular DNA from the same sample after extraction of the RNA an opportinity that discovered unexpectedly when developing our own RNA extraction method. To ensure proper blood collection we will use blood from a cohort of healthy volunteers prepared with different types of anticoagulant and treated with different enzymes and additives after collection. Blood from this cohort will be used for method development in this study and and for quality control purposes in this study and in other studies of extracellular RNA and DNA conducted in this group.

Type: Observational

open study

Behavioral and Neuroendocrine Effects of a Selective Kappa Opioid Receptor Antagonist
Rockefeller University Addictive diseases
This study will determine the impact of selective kappa-opioid receptor (KOPr) antagonism with the novel Lilly compound OpRA Kappa (LY2456302) in persons at specific stages in cocaine addiction trajectory compared to normal healthy volunteers. KOPr receptors (encoded by gene OPRK1) and their endogenous... expand

This study will determine the impact of selective kappa-opioid receptor (KOPr) antagonism with the novel Lilly compound OpRA Kappa (LY2456302) in persons at specific stages in cocaine addiction trajectory compared to normal healthy volunteers. KOPr receptors (encoded by gene OPRK1) and their endogenous neuropeptide ligands (the dynorphins encoded by gene PDYN) they are upregulated in addictive diseases and in other neuropsychiatric diseases. This upregulation may be due to chronic exposure to drugs of abuse such as cocaine due to stress exposure or as part of the etiology of the disease. Increased signaling through KOPr is thought to result in a relapse-prone state and to cause dysphoria / anhedonia in humans. KOPr antagonists thus represent a novel potential therapeutic strategy in cocaine addiction and related depressive symptoms a disease associated with massive public health morbidity and for which no pharmacotherapies exist

Type: Observational

open study

Isolation of human antibodies against Powassan virus for potential therapy vaccine and diagnostic purposes.
Rockefeller University Powassan virus
Powassan virus (POWV) is a virus spread by the same tick that spreads Lyme disease. When humans are bitten by an infected tick they can develop severe disease including encephalitis and POWV infection can be fatal. There is currently no specific treatment available. Ticks carrying the virus are found... expand

Powassan virus (POWV) is a virus spread by the same tick that spreads Lyme disease. When humans are bitten by an infected tick they can develop severe disease including encephalitis and POWV infection can be fatal. There is currently no specific treatment available. Ticks carrying the virus are found in several regions of the United States including the upper Midwest and the Northeast. There is concern that cases are increasing and POWV is emerging as a significant public health threat. Upon infection with germs such as bacteria and viruses the human body mounts a protective response including the production of special proteins called antibodies that block the germs and protect against similar infections in the future. Antibodies are made by special cells in the blood called B cells which have been shown to play important roles in protection from a number of viruses. B cells can be isolated from blood and analyzed to identify those that make the protective antibody for a specific virus. The genes that code for the protective antibody can be cloned and antibodies can be made outside the body. After they are purified the antibodies are further tested for their ability to bind to and block the virus's ability to infect cells. This has been a successful strategy to obtain HIV blocking antibodies which are being tested in clinical trials and have been found to be safe and to have significant activity against HIV. We propose to take a similar approach to isolate B cells and make antibodies that can block POWV. The antibodies could be useful for POWV treatment or the development of tests to aid diagnosis and may inform the design of vaccines against this emerging virus.

Type: Observational

open study

Characterizing the interaction between fibrin platelets and A? using an ex vivo clotting assay.
Rockefeller University Healthy volunteers
The Alzheimer's disease pathological peptide Aβ can affect blood clotting but a mechanism for this action is not fully understood. To investigate this effect further we will use an test tube assay for clotting to determine how Aβ interacts with both fibrin and platelets in human blood. Using this assay... expand

The Alzheimer's disease pathological peptide Aβ can affect blood clotting but a mechanism for this action is not fully understood. To investigate this effect further we will use an test tube assay for clotting to determine how Aβ interacts with both fibrin and platelets in human blood. Using this assay we have already observed that Aβ binds to a collagen surface when fibrin is present and that platelets bind to Aβ forming clots that are more stable than those formed in the absence of Aβ. We will use this clotting assay with real time imaging to explore how different structural forms and known mutants of Aβ alter clot formation and structure through their interaction with platelets and fibrin.

Type: Observational

open study

The Genetics of Developmental Face Blindness Prosopagnosia - a Clinical Pilot Project
Rockefeller University Prosopagnosia
Developmental face blindness also referred to as developmental Prosopagnosia is estimated to affect up to 2.5 percent of the general population causing severe consequences for the quality of lives of those affected. The condition is thought to result from genetic alterations which are currently unknown.... expand

Developmental face blindness also referred to as developmental Prosopagnosia is estimated to affect up to 2.5 percent of the general population causing severe consequences for the quality of lives of those affected. The condition is thought to result from genetic alterations which are currently unknown. To better understand the genesis of the condition and to evaluate potential strategies for treatment the current project aims to determine the genetic underpinnings of developmental prosopagnosia through genetic testing to identify causal mutations. This study will combine genetic testing with psychophysical testing of face recognition abilities. We will recruit individuals through the following major routes. (For the first route) We have created a recruitment flyer which we will distribute in the community. This flyer contains a summary regarding the study as well as the contact information of RU"s recruitment office. Additionally to this recruitment path we will utilize a preexisting online database (https://www.faceblind.org/contactus/index.html) established by Ken Nakayama and Bradley Duchaine one of our collaborators. Potential participants will be recruited from faceblind.org where they will have expressed their willingness to participate in research beforehand. Bradley Duchaine will distribute the study flyer to the individuals who expressed interest. By applying these two strategies we hope to reach a large number of individuals from diverse communities. Through the distribution of the same flyer to all potential participants we make sure that all individuals are instructed to contact the recruitment office and undergo the same enrollment processes. The RU recruitment team will screen individuals for eligibility record demographic information and their contact information and provided the participants with their unique code for identification and provide the test link leading to the online behavioral testing.

Type: Observational

open study

Peripheral Blood of Coronavirus Survivors to Identify Virus-Neutralizing Antibodies
Rockefeller University Coronavirus
The diversity of the antibody repertoire is generated by somatic recombination of immunoglobulin gene segments during early B cell development in the bone marrow. This random rearrangement process and the following antibody-maturation process generate a diverse repertoire of antibodies including antibodies... expand

The diversity of the antibody repertoire is generated by somatic recombination of immunoglobulin gene segments during early B cell development in the bone marrow. This random rearrangement process and the following antibody-maturation process generate a diverse repertoire of antibodies including antibodies that recognize pathogens (e.g. Coronaviruses in Coronavirus-infected individuals). In order to study the B cell repertoire of individuals who have been exposed to the Coronaviruses (a group of pathogenic viruses that includes Wuhan Coronavirus (nCoV-2019 recently renamed SARS-CoV-2 responsible for COVID-19 severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS]) we developed a method to clone and express antibodies from single human B cells at different stages of development or B cells that are specific for defined antigens (e.g. Coronavirus-spike proteins). Our goal with this study is to identify antibodies that target and potentially neutralize the Coronaviruses in individuals that have been exposed to the virus and have cleared the infection. We have previously shown that antibodies with potent neutralizing activity can be identified in HIV-infected and ZIKA-convalescent subjects. These antibodies can protect non-human primates from infection and are therefore highly valuable for HIV and ZIKA-vaccine design. Moreover we have shown that broadly neutralizing anti-HIV antibodies are able to suppress viral replication in HIV-infected humanized mice and non-human primates. As a result of these findings some of these antibodies are currently tested in clinical trials. Therefore we have a broad knowledge about anti-viral neutralizing antibodies. We want to apply this knowledge to identify Coronavirus-neutralizing antibodies that might be of potential benefit to protect and treat Coronavirus infection. In order to identify antigen-specific B lymphocytes single B cells will be isolated by fluorescence activated single cell sorting (FACS). Immunoglobulin heavy and light chain rearrangements will be cloned from purified individual cells and expressed in vitro to produce recombinant antibodies for further reactivity testing. Identified Coronavirus reactive antibodies will be further tested for Coronavirus-neutralization using in vitro assays and in vivo models but this will be performed by virologists elsewhere. This work will provide a valuable insight into specific B cell response against Coronavirus-infection. B cells and other cells of the immune system that will be analyzed will be obtained from a leukapheresis procedure or from a regular blood draw.

Type: Observational

open study

HIV-1 RNA Plasma Levels and HIV-1 Integration Sites in HIV-1 Infected Subjects
Rockefeller University Human Immunodeficiency Virus
HIV-1 integrates into host cellular DNA and can persist in a latent state. Antiretroviral therapy (ART) might alter HIV-1 integration site selection. Current antiretroviral regimens are effective in lowering circulating HIV-1 RNA levels to less than 20 copies/ml but in approximately 50% individuals persistent... expand

HIV-1 integrates into host cellular DNA and can persist in a latent state. Antiretroviral therapy (ART) might alter HIV-1 integration site selection. Current antiretroviral regimens are effective in lowering circulating HIV-1 RNA levels to less than 20 copies/ml but in approximately 50% individuals persistent low-level viremia can be detected despite years of suppressive ART. Moreover as anti-HIV-1 immune responses develop during the course of infection HIV-1 strains mutate to escape both humoral and cellular immune responses. This study aims at evaluating circulating HIV-1 RNA levels by a single copy assay as well as HIV-1 integration patterns of untreated and ART-treated subjects. We will also evaluate the presence of cell-free HIV-1 DNA in plasma from HIV-1-infected individuals which can serve as a biomarker of HIV-1-induced cell death. Lastly the study also aims at evaluating the sensitivity of viral strains to anti-HIV-1 broadly neutralizing antibodies.

Type: Observational

open study

Neuroendocrine Function in Healthy Volunteers and Volunteers with Cannabis Use Disorders
Rockefeller University Cannabis use disorder
How does the hypothalamic-pituitary-adrenal axis (HPA) system contribute to the use of cannabis the development of a cannabis use disorder and the relapse to cannabis use? The HPA axis is an important hormonal response system to stress. The actions of this hormone system normally are regulated to ensure... expand

How does the hypothalamic-pituitary-adrenal axis (HPA) system contribute to the use of cannabis the development of a cannabis use disorder and the relapse to cannabis use? The HPA axis is an important hormonal response system to stress. The actions of this hormone system normally are regulated to ensure that the body can respond quickly to stressful events and return to a normal state. The main determinants of HPA axis activity are genetic background early-life environment and current life stress. According to the National Institute on Drug Abuse (NIDA) marijuana use among high schoolers is at an all-time high. In 2018 43.6% 12th graders reported that they have tried marijuana. This percentage appears to be increasing; however the number of young people who believe regular marijuana use is risky is decreasing. As of October 2019 a total of 33 states District of Columbia Guam Puerto Rico and U.S. Virgin Islands have approved a comprehensive publicly available medical marijuana programs. However only 2.5% the population uses medical marijuana. Cannabis is widely available in the United States and use is becoming culturally acceptable (123). Additionally THC concentration has increased dramatically over the last 10 years from 8.9 0n 2008 to 17.1 0n 2017 (4). The mean THC:CBD ratio also rose substantially from 23 in 2008 to 104 in 2017.Therefore it is more relevant now than ever before to determine the effects of marijuana on the brain.

Type: Observational

open study

The Neural Basis of Face Recognition and Social Cognition: A Magnetic Resonance Imaging Study
Rockefeller University Healthy volunteers
We are interested in how we can recognize objects of the social world and react to them. As social animals particular objects of the outside world are of special significance to us. Faces arguably are the most important sources of social information in most if not all primate species. It may thus come... expand

We are interested in how we can recognize objects of the social world and react to them. As social animals particular objects of the outside world are of special significance to us. Faces arguably are the most important sources of social information in most if not all primate species. It may thus come as little surprise that special machinery in our brains is devoted to analyzing faces and making the results of these analyses available for a wide variety of behaviors. Some of these responses are automatic others voluntary but most of them fall into the category of social cognition or thinking about others. Because of this dedicated machinery we are extremely good at recognizing faces yet this is not the case for a fraction of the population estimated to be about one percent that is face blind prosopagnosic. People afflicted by this disorder an estimated one percent of the general population typically detect the presence of a face but cannot tell one individual from another which results in severe social difficulties. (In fact since many prosopagnosics are not aware of the fact of them being face blind we will not use prosopagnosia as an exclusion criterion during subject selection and since testing for prospagnosia takes much effort and time we will also not exhaustively test subjects prior to the experiments.) The goals of this study are to understand the functions of the different components of the face processing network its connectivity and embedding into other brain regions and the way that information about faces is used for behavioral responses. We will study these questions with magnetic resonance imaging (MRI) and behavioral testing. This technique allows us to obtain structural information about a subject"s brain its connectivity via diffusion tensor imaging (DTI which measures the molecular diffusion of water along neuronal pathways) and functional specializations via functional MRI (fMRI). Subjects will view pictures and movies of objects faces animals and animated characters while fixating on the screen or performing tasks requiring the detection of a particular stimulus or discrimination of stimuli. By contrasting activity elicited by different stimulus categories we can determine which regions of the brain respond more to stimuli of one category say faces than to those of another say houses. By combining this information across a number of studies we will gain insights into the functional organization of the brain for visual stimuli and in particular socially relevant stimuli. By combining this information with connectivity maps obtained by DTI or resting state connectivity analyses we can learn whether regions specialized for a particular stimulus category are preferentially coupled and form a network - and which other parts of the brain they are coupled to.

Type: Observational

open study

Genetic Predisposition to Appendicitis: A Pilot Study
Rockefeller University Appendicitis
7.5% the American population develop acute appendicitis making it the most common source of acute abdominal pain requiring surgery in the United States. By the end of the nineteenth century scientists and clinicians had already characterized the disease and recommended appendectomy as treatment [12].... expand

7.5% the American population develop acute appendicitis making it the most common source of acute abdominal pain requiring surgery in the United States. By the end of the nineteenth century scientists and clinicians had already characterized the disease and recommended appendectomy as treatment [12]. More than a century later this major surgical intervention remains the standard treatment for acute appendicitis with more than 300000 appendectomies performed annually in the United States alone [3]. The causes of the disease remain however largely unknown [8]. Recently clinical trials have demonstrated than in the majority of the cases appendectomy is actually not required and that antibiotics are an appropriate initial treatment for uncomplicated acute appendicitis [910]. This is a change of paradigm for the treatment of the disease but it also improves our understanding of the causes of acute appendicitis as it proves that infectious agents are involved which had been previously hypothesized by researchers [11]. Furthermore there is evidence in the medical literature of familial cases of appendicitis reported since 1937 [12]. Life habits and environmental factors cannot fully explain this pattern of familial aggregation and statistical models have estimated than between 25 to 50% the heritability of the disease is due to genetic transmission [13-15]. The infectious and genetic nature of acute appendicitis leads us to the hypothesis that genetic variations of the immune system are involved in its causes. Scientists have previously addressed appendicitis from a genetic prospective [[16]. These authors found a large region of the human genome involved in the heritability of the disease. However there are no published studies using modern high-throughput sequencing methods which would help us look at genetic content at a finer resolution and find specific candidate genes involved in the transmission of the disease. In this study we plan to use whole exome sequencing in patients of interest. Whole exome sequencing has proven to be a reliable tool to extract genomic variations in the coding regions of the human genome [1718]. We will use this technique to highlight any candidate genes or events in the subjects" genome that may be involved in predisposition to appendicitis. Finding the genetic factors involved in the etiology of acute appendicitis will help us improve our understanding of the disease but due to the infectious nature of appendicitis it will also improve our understanding of the whole human immune system.

Type: Observational

open study

Studies of Long-Acting Opioid Metabolism Disposition Drug Interactions and Effects
Rockefeller University Addictive diseases
The overall goals of this continuing research are (1) to improve medical care of patients in maintenance treatment for heroin addiction by increasing knowledge about metabolism and effects of methadone and buprenorphine as prototypic long-acting narcotic agonist agents; (2) to develop specifications... expand

The overall goals of this continuing research are (1) to improve medical care of patients in maintenance treatment for heroin addiction by increasing knowledge about metabolism and effects of methadone and buprenorphine as prototypic long-acting narcotic agonist agents; (2) to develop specifications for alternative treatment agents both for opiate dependency and ultimately effective medications for cocaine dependency or mixed addictive disease; and (3) to gain increased information concerning tolerance and dependence particularly as related to -the metabolism distribution persistence and physiological effects of narcotic drugs in the body and the mechanisms of addiction; (4) to determine the impact of drugs of abuse specifically opiates and cocaine on the medical status of drug abusers including both direct drug effects which may alter normal physiology or may cause toxic responses as well as indirect drug effects including the abnormal physiological and pathological states caused by the sharing of unsterile injection equipment and altered lifestyle; the effects of treatment with a variety of specific pharmacological agents or drug free treatment on the natur-al history of the chronic diseases such as hepatitis B C and HIV infection which have occurred prior to or less often during treatment which may be altered by treatment. All of these studies will contribute to an increased knowledge about the natural history of specific addictive diseases in pharmacologic treatment in behavioral treatment or in no treatment.

Type: Observational

open study

Identifying the Initial Triggers of Multiple Sclerosis (MS)
Rockefeller University Multiple Sclerosis
Multiple sclerosis (MS) is a disease of the brain in which blood vessels and the fatty tissue that insulates nerve cells myelin are damaged. How the brain tissues are damaged remains unknown. We have identified a toxin that is produced by the intestinal bacterium Clostridium perfringens as a possible... expand

Multiple sclerosis (MS) is a disease of the brain in which blood vessels and the fatty tissue that insulates nerve cells myelin are damaged. How the brain tissues are damaged remains unknown. We have identified a toxin that is produced by the intestinal bacterium Clostridium perfringens as a possible cause of MS. This bacterial toxin named epsilon toxin specifically damages brain blood vessels and brain myelin. Additionally we have found that epsilon toxin damages immune cells in the blood called T cells. In this study we wish to collect blood from MS patients who are currently experiencing symptoms. We will test these blood samples for the presence of epsilon toxin. Damage to T cells by epsilon toxin also causes indirect damage to neighboring red blood cells the cells that carry oxygen in the blood. We have found that copper and iron released from toxin exposed T cells causes red blood cells to swell and breakdown more easily than normal. For these reasons we also wish to determine the mechanism by which copper and iron release is triggered by T cell toxin exposure.

Type: Observational

open study

Investigating the Impact of Race on Gene-Expression Profiles in HIV Associated Neurocognitive Disorders
Rockefeller University Human Immunodeficiency Virus
HIV-Associated Neurocognitive Disorders (HANDs) are a pervasive and debilitating complication of HIV infection with an estimated prevalence of 30-45%. The identification of robust validated specific and sensitive biomarkers for HAND that do not require invasive CSF sampling has been elusive and is of... expand

HIV-Associated Neurocognitive Disorders (HANDs) are a pervasive and debilitating complication of HIV infection with an estimated prevalence of 30-45%. The identification of robust validated specific and sensitive biomarkers for HAND that do not require invasive CSF sampling has been elusive and is of paramount importance. However unrecognized racial differences in gene expression could significantly impact the predictive value of biomarkers of HAND if applied to populations in which they have not been developed or validated. We hypothesize that significant racial differences will be identified in the peripheral blood single-cell based gene-expression profiles of HAND. We further hypothesize that these differences may be largely attributed to delays in viral suppression and delayed/decreased access to care. To test these hypotheses we will use multivariate modeling to determine the relative influence of clinical and sociodemographic variables and social determinants of health on unbiased single-cell based gene transcriptional profiles in the peripheral blood of HIV-positive virally suppressed African American and Caucasian cohorts with and without HAND.

Type: Observational

open study

Bactericidal Assays to Determine Antibody Effiicacy
Rockefeller University Healthy volunteers
Our laboratory develops methods to control infections by gram-positive bacteria. In the process we need to test what we have developed (vaccine-induced antibodies recombinant antibodies chimeric antibodies) in a human system. One of the best systems is human blood which contains white blood cells that... expand

Our laboratory develops methods to control infections by gram-positive bacteria. In the process we need to test what we have developed (vaccine-induced antibodies recombinant antibodies chimeric antibodies) in a human system. One of the best systems is human blood which contains white blood cells that phagocytize disease bacteria. Therefore to test the products we have developed we need to take blood from volunteers and use the white blood cells in that blood to test our products to determine if they enhance the ability of the white cells to kill the bacteria and also evaluate the immune response by these WBC to the bacteria. In some cases we will compare the activity of the product following previous activation of the WBC with the person"s own bacteria to that with no previous encounter with the bacteria. To this end the donor will be swabbed. The swabbed bacteria from the skin (forearm) and the nares will be grown and used with the above assay.

Type: Observational

open study

Healthy Volunteers for the Human Genetics of Infectious Diseases (HGID)
Rockefeller University Healthy volunteers
Our laboratory is working to find mutations in genes that may cause severe infectious diseases in adults. We will draw blood and take a small piece of skin (a biopsy) from ten healthy volunteers in order to support research studies being conducted in the Casanova Lab of Human Genetics of Infectious Diseases.... expand

Our laboratory is working to find mutations in genes that may cause severe infectious diseases in adults. We will draw blood and take a small piece of skin (a biopsy) from ten healthy volunteers in order to support research studies being conducted in the Casanova Lab of Human Genetics of Infectious Diseases. We will perform experiments to test the mutations that we find in patients with severe bacterial viral and fungal illnesses. The samples collected from healthy volunteers will be compared to those taken from patients with severe infectious diseases. Blood samples will be used as controls for but not limited to the following: for activation production of cytokines molecular expression cellular differentiation of either whole blood or just the white blood cells (leukocytes). A small skin biopsy (less than 2mm) will be taken from under the arm and will be used to generate fibroblast and keratinocyte cultures which will be immortalized and used as controls for but not limited to the following: stimulation of cytokine production protein expression and response to infection with viruses and bacteria. The fibroblasts may also be reprogrammed to become stem cells from which we will derive cells of the central nervous system and the lung for research studies.

Type: Observational

open study

Molecular and Neuroendocrine Profile in Normal Healthy Volunteers and Volunteers with Specific Addictions
Rockefeller University Addictive diseases
How does the atypical stress responsivity to stress and stressors contribute to the acquisition and persistence of and relapse to the use of illicit drugs (such as heroin and cocaine) and alcohol? The central hypothesis of this project is that atypical stress responsivity to stress and stressors contributes... expand

How does the atypical stress responsivity to stress and stressors contribute to the acquisition and persistence of and relapse to the use of illicit drugs (such as heroin and cocaine) and alcohol? The central hypothesis of this project is that atypical stress responsivity to stress and stressors contributes to the acquisition and persistence of and relapse to the use of illicit drugs (such as heroin and cocaine) and alcohol. We hypothesize and now have shown that the endogenous opioid system significantly contributes to the normal regulation of the hypothalamic-pituitary-adrenal (HPA) axis in humans. The HPA axis is a major contributor to the stress response in humans and all mammalian species. In humans it is a readily accessible locus for documenting and testing alterations in stress responsivity related to the addictive diseases. Previous work in this laboratory has established that opiate addiction atypical stress-responsivity of the HPA axis and the endogenous opioid system are interrelated. Our laboratory continues to examine the role of the endogenous opioid system during different stages of addictive diseases (including vulnerability acquisition persistence withdrawal and protracted abstinence).

Type: Observational

open study

Derivation and Characterization of Keratinocytes in Healthy Volunteers
Rockefeller University Fanconi anemia
Fanconi anemia is an inherited genetic disorder which results in a decrease in the body"s ability to repair damage to DNA. The main features of the disorder are bone marrow dysfunction and cancer predisposition. Squamous cell carcinomas of the head and neck are the most commonly diagnosed solid tumors... expand

Fanconi anemia is an inherited genetic disorder which results in a decrease in the body"s ability to repair damage to DNA. The main features of the disorder are bone marrow dysfunction and cancer predisposition. Squamous cell carcinomas of the head and neck are the most commonly diagnosed solid tumors in patients with Fanconi anemia. These tumors originate from skin cells called keratinocytes. In patients with Fanconi anemia the tumors are more aggressive and develop at an earlier age than in persons without the disorder. The tumors are also more difficult to treat in patients with Fanconi anemia since they experience extreme toxicity from standard therapies such as chemotherapy and radiation. Prevention of this type of cancer is therefore critically important. Understanding the steps in the development of squamous cell carcinomas and the reasons why the cells involved become cancerous can help us to develop ways to prevent this process from occurring. Our current study aims to grow and characterize keratinocyte cells from healthy individuals. Eventually we will also study these cells from patients with Fanconi anemia. By doing this we hope to learn why these cells are particularly susceptible to developing tumors in the context of the genetic changes seen in Fanconi anemia. Since the DNA damage repair pathways that are dysfunctional in Fanconi anemia are present in all humans the information we gain will also help us to understand more about cancer susceptibility in the general population.

Type: Observational

open study

Discovering novel therapeutic options for HIV-Associated Neurocognitive Disorders (HAND) by exploiting...
Rockefeller University Human Immunodeficiency Virus
HIV-Associated Neurocognitive Disorders (HAND) are an important clinical complication of HIV infection and can result in an array of cognitive behavioral and motor deficits. With an estimated prevalence of 30-45 0n the combination antiretroviral therapy (cART) era HANDs are pervasive with significant... expand

HIV-Associated Neurocognitive Disorders (HAND) are an important clinical complication of HIV infection and can result in an array of cognitive behavioral and motor deficits. With an estimated prevalence of 30-45 0n the combination antiretroviral therapy (cART) era HANDs are pervasive with significant potential to adversely affect quality of life morbidity and mortality. At present no adjunctive therapies for HAND exist making the need for their development of paramount clinical importance. HIV is postulated to cross the blood-brain barrier (BBB) via the infiltration of infected monocytes CD4+ T lymphocytes or as cell-free virus. The integrin α4β1 (VLA-4) is an integrin dimer often referred to as a marker of CNS homing. VLA-4 is widely expressed on leukocyte plasma membranes and binds the integrin receptor vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. Antibodies against the α4 subunit of VLA-4 have been shown to block monocyte/macrophage and SIV virus traffic to the brain and stabilize CNS injury in a rhesus macaque model of HIV infection. We hypothesize that VLA-4 expressing leukocytes are enriched for cells trafficking to the CNS and the transcriptional profiling of these cells in the periphery of HAND patients can identify genes signaling pathways and ultimately small molecule candidates for therapeutic development in HAND. To explore this hypothesis we performed preliminary experiments employing transcriptome sequencing (RNA-seq) of purified VLA-4 expressing CD14+ monocytes and CD4+ T cells from the PBMC of chronically infected HIV positive subjects on suppressive cART. We identified a number of highly differentially expressed genes between individuals with HAND (n=6) and those with normal neurocognitive function (NCN) (n=6) including some (e.g. CCL2) also referred to as monocyte chemoattractant protein 1 (MCP-1) that have been long implicated in HAND pathogenesis. This led to a preliminary "HAND gene-expression signature". These exciting results will be expanded upon in this 3-year proposal. Here we will seek to: AIM 1) Enroll and immunologically phenotype a larger cohort of HIV-positive individuals. We will perform neuropsychological testing (NPT) to identify 15 individuals with HAND and 15 individuals with NCN. Novel flow cytometry experiments will determine the distribution of VLA-4 expression on leukocytes from paired cerebrospinal fluid (CSF) and blood in treated suppressed HIV. A third control group of 15 HIV-negative individuals will be similarly characterized. Potential relationships between levels of VLA-4 expression and NPT performance will be examined through multivariate modeling; and AIM 2) Validate our preliminary HAND gene-expression signature. We will perform RNA-seq analysis on RNA from VLA-4 expressing CD14+ monocytes and CD4+ T cells from peripheral blood obtained from all participants enrolled in AIM 1 apply GSEA pathway analysis and confirm candidate genes using q-PCR. In this way we expect to identify robust candidate disease biomarkers and exploitable molecular targets for therapy. Additionally using the Broad Institute Connectivity map we will identify therapeutic candidate molecules for reversal of the HAND signature in future studies. In summary we propose a rational integrated clinical systems biology molecular approach that has the potential to transform the treatment landscape for an important HIV co-morbidity.

Type: Observational

open study

The human immune response to Staphylococcus aureus
Rockefeller University Staphylococcus aureus
Staphylococcus aureus (SA) is a leading cause of morbidity mortality and as a result it is responsible for a marked economic burden on today"s health care system. Infections with SA that are resistant to Methicillin antibiotic (MRSA) are very common and are a major part of this burden. 30% of the population... expand

Staphylococcus aureus (SA) is a leading cause of morbidity mortality and as a result it is responsible for a marked economic burden on today"s health care system. Infections with SA that are resistant to Methicillin antibiotic (MRSA) are very common and are a major part of this burden. 30% of the population are colonized with S. aureus so at least theoretically their immune system is constantly exposed to the bacteria and expected to induce protective immunity. However at the same time 30% of the population experiencing an infection with S. aureus will be afflicted with recurrent infections with this bacterium and despite previous exposure. Developing a vaccine would be an ideal solution for prevention of these infections. However despite intensive study in the last 3 decades a successful vaccine against S.aureus is still unavailable. For developing and designing an efficient vaccine a better understanding of the immune response to S. aureus is needed..For many yearsthe concept was that B cell responses and antibody production are enough for protection against S.aureus. In recent years direct evidence from KO mice as well as evidence from humans with primary immune deficiency demonstrates that CD4 Th1 and Th17 immune responses are necessary for protection from S. aureus. Nevertheless our recent results demonstrate that the Th1 and Th17 response to the various S. aureus strains varied extensively in response to in-vitro stimulation. Further wide variability was also inspected in IgG expression by proliferating B cells in response to the different strains. We could show that mobile genetic elements carried by phages are responsible for a significant portion of this immune response variability. These findings are bringing up the possibility that the strain specificity is a new factor that might need to be taken into account when we are evaluating protection. At this time point what is not known/understood and what we want to clarify in the current study is: (i) Whether previous exposure to various strains results in different level of protective memory. (ii) How immune memory induced by exposure to one strain affect the ability to respond to other strains of S. aureus.

Type: Observational

open study

Assessment of Inflammatory Mediators in Hidradenitis Suppurativa
Rockefeller University Hidradenitis suppurativa
Hidradenitis Suppurativa (HS) is a severe skin disease causing painful swelling and foul smelling weeping wounds in the armpits groin and under the breasts. It is a long-term condition with few effective treatments available. It is also unpredictable which treatments will be effective for which patients.... expand

Hidradenitis Suppurativa (HS) is a severe skin disease causing painful swelling and foul smelling weeping wounds in the armpits groin and under the breasts. It is a long-term condition with few effective treatments available. It is also unpredictable which treatments will be effective for which patients. Researchers have attempted to describe "subtypes" of HS but none have been effective in predicting which patients will respond to specific treatments. Our research involves asking patients with HS to donate small samples of skin fat blood and pus to find out why certain patients develop HS and hopefully be able to give patients the most effective treatment first rather than trialling many different treatments with no guarantee which will work best.

Type: Observational

open study

Human Genetic Correlates of the Addictive Diseases
Rockefeller University Addictive diseases
Studies of genetic epidemiology have demonstrated that there exists a heritable contribution to individual variability in vulnerability to specific addictions. The overall goal of this project is to determine which variants of specific genes affect vulnerability to specific addictions. Our primary focus... expand

Studies of genetic epidemiology have demonstrated that there exists a heritable contribution to individual variability in vulnerability to specific addictions. The overall goal of this project is to determine which variants of specific genes affect vulnerability to specific addictions. Our primary focus is on opiate addiction but addiction to other drugs and alcohol is also under study. Study subjects are thoroughly characterized using several structured and semi-structured instruments. We use both case-control and family-genetic approaches. Hypothesis driven selection of genes for study is used as well as positional methods using a variety of genetic markers to identify additional genes and gene variants contributing to addiction vulnerability.

Type: Observational

open study

Assessing Adipose Tissue and Metabolic Profiles of Childhood Cancer Survivors after Radiation Therapy:...
Rockefeller University Childhood cancer
Due to advances in multimodality therapy 5-year survival rates for childhood cancer now exceed 80%. Survivors however face an increased lifelong risk of multiple treatment-related complications or "late effects" including insulin resistance metabolic syndrome and diabetes mellitus. Abdominal and total... expand

Due to advances in multimodality therapy 5-year survival rates for childhood cancer now exceed 80%. Survivors however face an increased lifelong risk of multiple treatment-related complications or "late effects" including insulin resistance metabolic syndrome and diabetes mellitus. Abdominal and total body irradiation have been implicated as key mediators of this process but the precise pathways by which they lead to metabolic derangement are poorly understood. Optimal methods for early detection also remain unknown. Recent evidence has suggested that abnormalities of adipose tissue or fat may play an important role in the pathogenesis of metabolic complications in childhood cancer survivors. The current project seeks to assess whether adipose tissue exposed to radiation demonstrates molecular and morphological changes when compared to adipose tissue that has never been exposed to radiation.

Type: Observational

open study

Developing Directly Reprogrammed Human Neurons to Investigate the Molecular Basis of Neurodegeneration...
Rockefeller University Human Immunodeficiency Virus
The prevalence of HIV-1 associated neurocognitive disorders (HANDs) is 30% . Advancing age is strongly associated with increased HAND prevalence and investigating the molecular basis of synaptodendritic injury and neurocognitive decline in this context... expand

The prevalence of HIV-1 associated neurocognitive disorders (HANDs) is 30% . Advancing age is strongly associated with increased HAND prevalence and investigating the molecular basis of synaptodendritic injury and neurocognitive decline in this context is paramount. Recently the ability to generate directly induced neurons (iNs) from patient-derived fibroblasts has been demonstrated. Unlike the immature neuronal populations generated from induced pluripotent stem cells (iPSCs) iNs reportedly retain aging-associated characteristics of the donor. In this proposal we aim to develop directly induced neurons (iNs) from HIVnegative individuals that retain age-associated transcriptional signatures. We will then determine if directly induced neurons (iNs) derived from HIV-positive individuals reveal age- and additional HIV disease-associated transcriptional signatures.

Type: Observational

open study

When the Kidney Reacts to Nutritional Changes
Rockefeller University Prehypertension
Hypertension is one of the leading causes of morbidity and mortality in the industrialized world, attributed mostly to modifiable lifestyle factors. Aspects that are controlled by patients include physical activity, smoking, alcohol consumption, and nutrition. The DASH (Dietary... expand

Hypertension is one of the leading causes of morbidity and mortality in the industrialized world, attributed mostly to modifiable lifestyle factors. Aspects that are controlled by patients include physical activity, smoking, alcohol consumption, and nutrition. The DASH (Dietary Approach to Stop Hypertension) diet is a proven effective intervention in lowering blood pressure in multiple populations. In this proof of concept study, volunteers with untreated stage 1 hypertension, defined as mild high blood pressure with numbers in the range of 130 - 139 over 80 - 89, will receive a DASH-based menu during 5 days of hospitalization, during a weekend at home where they will continue the menu, another 5 days as inpatients, followed by a weekend at home on the same menu, and the return to the inpatient unit for an additional day for final testing. Throughout the intervention period, participants will be followed clinically and undergo repeated laboratory testing. The aim of this project is to characterize changes in urine electrolytes and exosome protein abundance pattern during nutritional changes, shifting from a "westernized diet" to a DASH diet.

Type: Interventional

Start Date: Feb 2020

open study