The Rockefeller University

Hypertensive disorders of pregnancy (including preeclampsia) are among the leading causes of pregnancy complications and maternal deaths worldwide. They also increase the risks to the babies. Numerous interventions have been suggested in order to reduce the rate of preeclampsia. Low-dose aspirin is the most beneficial prophylactic approach in this regard. Nevertheless, aspirin failure is not uncommon. The genetic, laboratory, and clinical factors associated with low-dose aspirin failure in the prevention of preeclampsia are largely unknown. The presence of a genetic variant in PAR4 receptor expressed on platelets, is associated with increased platelet function and possibly with aspirin failure.

Type: Interventional

Start Date: Apr 2023

open study

Blood contains red blood cells, white blood cells, and platelets, as well as a fluid portion termed plasma. We primarily study blood platelets, but sometimes we also analyze the blood of patients with red blood cell disorders (such as sickle cell disease), white blood cell disorders, and disorders of the blood clotting factors found in plasma. Blood platelets are small cell fragments that help people stop bleeding after blood vessels are damaged. Some individuals have abnormalities in their blood platelets that result in them not functioning properly. One such disorder is Glanzmann thrombasthenia. Most such patients have a bleeding disorder characterized by nosebleeds, gum bleeding, easy bruising (black and blue marks), heavy menstrual periods in women, and excessive bleeding after surgery or trauma. Our laboratory performs advanced tests of platelet function and platelet biochemistry. If we find evidence that a genetic disorder may be responsible, we analyze the genetic material (DNA and RNA) from the volunteer, and when possible, close family members to identify the precise defect.

Type: Observational

Start Date: Sep 2005

open study

A promising approach to correct the metabolic dysfunction associated with obesity is to activate brown fat non-shivering thermogenesis (NST). A critical limitation with NST as a therapeutic option, however, is that this beneficial process is silenced under human physiological temperature conditions and the mechanisms of how this occurs is unknown. This study will be the first to identify human NST silencing factors that may be targeted for the treatment of obesity and metabolic disorders.

Type: Interventional

Start Date: Aug 2024

open study

'The reason for doing this research is to better understand hidradenitis suppurativa also known as HS or acne inversa. HS involves skin folds and causes swelling of the skin and surrounding tissues pain and foul-smelling discharges. These changes normally occur in the armpits groin and under the breasts however they can occur anywhere.  'Effective treatment options are lacking. Recently clinical trials conducted by researchers from our lab found Brodalumab was an effective drug for this disease. Common treatments for HS include combinations of antibiotics retinoids and the biologic agent Adalimumab/Humira. Yet as these treatments are frequently unsatisfactory many severe patients eventually undergo extensive surgery to remove areas with active skin lesions. Still even after extensive surgery there may be a relapse of the disease in other areas. There is thus a great need to better understand the disease and the drivers of the inflammation in HS that will allow the develop of new therapeutics in the future.  'To do that we will enroll HS patients with different symptoms and severity levels. We will study their disease with one or more of the following assessment tools: blood testing skin biopsies skin tape-strips clinical assessment ultrasound tissue impedance microbiological sampling and clinical photography-before during and after therapy. However we will not be prescribing medication and will not take over patients' medical care.

Type: Observational

open study

The reason for doing this research is to study the nature diagnosis and treatment of individuals affected with the genetic disease Fanconi anemia an inherited disorder that leads to bone marrow failure (aplastic anemia) and cancer development.  In most cases it is a recessive disorder: if both parents carry a defect (mutation) in the same Fanconi anemia gene each of their children has a 25% chance of inheriting the defective gene from both parents.  When this happens the child will have Fanconi anemia.  Patients may have a variety of birth defects and may eventually develop acute myelogenous leukemia (AML) head and neck gynecological and/or gastrointestinal cancer.  The researchers doing the study will collect information about the medical history genetics clinical course blood test results treatment complications and social issues of Fanconi anemia.  Information about relatives of Fanconi anemia patients will also be collected.  A purpose of this project is to develop a detailed listing or `registry' of people who may have Fanconi anemia and their close family members. Tissue samples are collected in a repository in order to study the genotype of the study subjects for geneotype/phenotype correlation and to understand why bone marrow and cancer develop.  Using patient samples we want to understand the disease so we can develop new preventive and treatment strategies.

Type: Observational

open study

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

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

Our laboratory is working to find mutations in genes that may cause severe infectious diseases. We will draw blood and obtain a skin biopsy sample from 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 fungal and other 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 skin biopsy (up to 6mm) will be obtained and will be used to generate fibroblast and keratinocyte cultures. Fibroblasts and keratinocytes may 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. Some experiments including single-cell RNA sequencing (scRNAseq) require fresh skin tissue. A 6mm biopsy will enable us to conduct multiple techniques in parallel including imaging studies (i.e. hyperion) and scRNAseq on the same individual and the same tissue site. Imaging studies will allow us to characterize the cellular architecture of the tissue and scRNAseq to establish the characteristics of the stratified epithelium (i.e. basal and differentiated keratinocytes) and to define which is the target cell of the pathogen in infected individuals vs. healthy controls. This tissue-based approach enables us to compare the interaction of the cells in the tissue in healthy controls vs. individuals with infectious diseases to better understand the pathophysiology of the disease.

Type: Observational

open study

Antibodies are the primary mediators of the protection against infection provided by vaccination. Antibodies become most powerful after the B cells that produce them undergo an evolutionary process called affinity maturation, in which antibodies increase their ability to bind to their targets, and thus neutralize pathogens. Affinity maturation occurs in structures within secondary lymphoid organs (for example lymph nodes or tonsils) known as germinal centers. Germinal centers are well known to be triggered by the first dose of vaccines, generating affinity matured plasma cells (B cells that secrete antibody into serum) and memory B cells, which can be converted into plasma cells by booster doses of vaccine. However, it is not fully understood the extent to which memory B cells can return to germinal centers again upon vaccine boosting. Such return would be very important to allow B cells, for example, to adapt to emerging variants of viruses such as influenza or SARS-CoV-2. This study will involve acquiring samples of B cells from germinal centers that form in response to vaccination with the highly effective hepatitis B vaccine. These cells will be analyzed to determine what fraction of them are memory B cells that returned to germinal centers upon boosting, information that is key to knowledge of how vaccine boosters work. Understanding the "rules" that govern how and when memory B cells choose to return to germinal centers in an effective vaccine such hepatitis B could help efforts to develop effective vaccination against more challenging, rapidly mutating viruses, such as influenza, HIV, and hepatitis C.

Type: Interventional

Start Date: Dec 2022

open study