A5010817079- Neuroinflammation and Neurodegeneration Mechanisms
- Single-cell and spatial transcriptomics
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Alzheimer's disease research and treatments
- Atherosclerosis and Cardiovascular Diseases
- Immune cells in cancer
- Multiple Sclerosis Research Studies
- Nuclear Receptors and Signaling
- Gene expression and cancer classification
- Bioinformatics and Genomic Networks
- Neurological Disease Mechanisms and Treatments
- IL-33, ST2, and ILC Pathways
- Cytokine Signaling Pathways and Interactions
- interferon and immune responses
- Inflammation biomarkers and pathways
- Diabetes and associated disorders
- RNA Research and Splicing
- Viral Infections and Immunology Research
- Liver Disease Diagnosis and Treatment
- Acute Lymphoblastic Leukemia research
- Cellular Mechanics and Interactions
- Cytomegalovirus and herpesvirus research
- Epigenetics and DNA Methylation
Washington University in St. Louis
2020-2023
Brigham and Women's Hospital
2014-2022
Columbia University Irving Medical Center
2017-2020
Harvard University
2014-2018
Broad Institute
2015-2017
Rush University Medical Center
2016
Massachusetts General Hospital
2016
Colby–Sawyer College
2013
We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects established a reference map the architecture MS that includes 200 autosomal susceptibility variants outside major histocompatibility complex (MHC), one chromosome X variant, 32 within extended MHC. used an ensemble methods to prioritize 551 putative genes implicate innate adaptive pathways distributed across cellular components immune system. Using expression profiles from purified human microglia, we...
Abstract The extent of microglial heterogeneity in humans remains a central yet poorly explored question light the development therapies targeting this cell type. Here, we investigate population structure live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single RNA sequencing, find that some subsets are enriched for disease-related genes signatures. We confirm presence four these subpopulations histologically illustrate...
With a rapidly aging global human population, finding cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding what constitutes phenotype aged microglia-the cell type that been strongly implicated genetic studies in pathogenesis age-related disease. Here, we establish set genes is preferentially expressed microglia brain. This HuMi_Aged gene captures unique phenotype, which confirm at protein level....
A microglial-like cellular model can be used to identify functional consequences of genetic variants associated with neurodegenerative disease.
Abstract: We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects 68,284 control establish a reference map the architecture MS that includes 200 autosomal susceptibility variants outside major histocompatibility complex (MHC), one chromosome X variant, 32 independent associations within extended MHC. used an ensemble methods to prioritize up 551 potentially associated genes, implicate innate adaptive pathways distributed across cellular components immune system....
Complexity of cell-type composition has created much skepticism surrounding the interpretation bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate proportions from gene expression data blood samples, but their performance when brain is unclear. Here, we generated an immunohistochemistry (IHC) dataset for five major cell-types 70 individuals, who also cortical data. With IHC as benchmark, this resource enables...
The Genes and Environment in Multiple Sclerosis project establishes a platform to investigate the events leading multiple sclerosis (MS) at‐risk individuals. It has recruited 2,632 first‐degree relatives from across USA. Using an integrated genetic environmental risk score, we identified subjects with twice MS when compared average family member, report initial incidence rate these that is 30 times greater than of sporadic MS. We discuss feasibility large‐scale studies asymptomatic leverage...
Given evidence from genetic studies, we hypothesized that there may be a shared component to the role of myeloid function in Parkinson and Alzheimer disease (PD AD) assessed whether PD susceptibility variants influenced protein expression well-established AD-associated genes human monocytes.We repurposed data which AD-related proteins CD33, TREM1, TREM2, TREML2, TYROBP, PTK2B were measured by flow cytometry monocytes 176 participants PhenoGenetic Project (PGP) Harvard Aging Brain Study....
Abstract Recent studies of bulk microglia have provided insights into the role this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding diversity human microglial states remains limited; are highly plastic multiple different roles, making extent phenotypic heterogeneity a question, especially light development therapies targeting type. Here, we investigated population structure by single-cell RNA-sequencing. Using surgical-...
NK effector functions can be triggered by inflammatory cytokines and engagement of activating receptors. cell production IFN-γ, an important immunoregulatory cytokine, exhibits activation-specific IFN-γ regulation. Resting murine cells exhibit metabolic requirements for production, which are reversed receptor-mediated stimulation following IL-15 priming. Although both cytokine receptor leads to similar protein only upregulates Ifng transcript, suggesting that is translationally regulated...
Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into activator upon activation the canonical pathway. Genome-wide association studies rheumatoid arthritis (RA) identified susceptibility locus, rs874040(CC), which implicated RBPJ gene. Here, chromatin state mapping generated using chromHMM algorithm reveals...
Abstract Complexity of cell-type composition has created much skepticism surrounding the interpretation brain bulk-tissue transcriptomic studies. We generated paired tissue genome-wide gene expression data and immunohistochemistry data, enabling us to assess statistical methods for modeling estimating cellular heterogeneity in brain. demonstrate that several algorithms rely on single-cell cell-sorted define cell marker sets yield accurate relative absolute estimates constituent proportions.
Abstract Recent studies identifying expression quantitative trait loci (eQTLs) in immune cells have uncovered important links between disease risk alleles and gene trends monocytes, T other cell types. However, these are generally done with young, healthy subjects, limiting the utility of their findings for age-related conditions such as Alzheimer’s (AD). We performed RNA sequencing on four T-cell subsets genome-wide genotyped well-characterized AD subjects age- sex-matched controls from...
Natural killer (NK) effector functions can be triggered by inflammatory cytokines and engagement of activating receptors. NK cell production IFN-γ, an important immunoregulatory cytokine, exhibits activation-specific IFN-γ regulation. Resting murine cells exhibit metabolic requirements for production, which are reversed receptor-mediated stimulation following IL-15 priming. While both cytokine receptor leads to similar protein only upregulates Ifng transcript, suggesting that is...
Abstract Cell adhesion makes possible the development of tissues and organs. It has thus been an important topic in biomedical research, cancer research particular. One method used to quantify cell adhesion, dual pipette assay, shown persistent variability force required separate adherent cells despite efforts minimize through strict protocols assay automation. We are using FUCCI (fluorescence ubiquitination cycle indicator) determine if cell-cycle dependent changes might account for...
Abstract Recent studies identifying expression quantitative trait loci (eQTL) in immune cells have uncovered important links between disease risk alleles and gene trends monocytes, T cells, other cell types. However, these are generally done with young, healthy subjects, limiting the utility of their findings for age-related conditions such as Alzheimer’s (AD). We performed RNA sequencing on four subsets genome-wide genotyped well-characterized AD subjects age- sex-matched controls from...
Abstract Natural killer (NK) cells are innate lymphocytes important for the control of infections and tumors. Their effector functions can be triggered by inflammatory cytokines or engagement ITAM-bearing activating receptors. We previously reported that IFN-γ production through ITAM signaling is metabolism-dependent in naïve NK cells. However, cytokine stimulation priming with high-dose IL-15 prior to leads metabolism-independent production. While both receptor similar protein production,...