权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Functional mapping of ex-regulatory T cell phenotypic diversity

前调节性T细胞表型多样性的功能图谱

基本信息

批准号：
10526432
负责人：
Cody Mowery
金额：
$ 5.27万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2024-05-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10526432
关键词：
Activities of Daily Living Affect Autoimmune Autoimmunity CD4 Positive T Lymphocytes Cell Compartmentation Cell Lineage Cell physiology Cells Childhood Chromosome Mapping Clinic Clinical Colon Complex Computational Biology Cues Data Data Set Development Diffusion Disease Doctor of Philosophy Environment Equilibrium Fellowship Flow Cytometry Fostering Future Gene Expression Gene Expression Profile Generations Genetic Genetic Engineering Genetic Predisposition to Disease Genetic Screening Genetic study Genomic approach Heterogeneity Homeostasis Human Immune Immune System Diseases Immune Tolerance Immunologics Immunologist Immunology In Vitro Individual Inflammation Inflammatory Interleukin-4 Interleukin-6 Laboratories Lung Lymphoid Tissue Malignant Neoplasms Maps Mediating Mentorship Molecular Mus Nature Nuclear Organ Outcome Pathologic Pattern Pediatric Hospitals Peripheral Phenotype Population Preceptorship Predisposition Process Proteins Regulator Genes Regulatory T-Lymphocyte Reporter Role Runaway Secure Signal Transduction T-Cell Development T-Lymphocyte T-cell inflamed Technology Thymus Gland Tissues Training Work autoimmune inflammation autoimmune pathogenesis autoinflammation base career computerized tools cytokine effector T cell functional genomics genetic disorder diagnosis genetic manipulation in silico in vitro Assay inflammatory milieu innovation innovative technologies interest knockout gene lymph nodes novel peripheral tolerance phenotypic biomarker polarized cell prevent programs single-cell RNA sequencing transcription factor transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Regulatory and effector T cells serve distinct immunological roles that contribute to immune homeostasis. Whereas effector T cells have the functional capacity to protect the host from infectious threats and cancer, regulatory T cells (Tregs) are suppressive in nature and prevent runaway effector T cell-mediated inflammation and autoimmunity. Although these are distinct cell lineages determined primarily during thymic selection, it is now understood that the two can interconvert – T cells can assume regulatory phenotypes in the periphery, and Tregs may lose suppressive capacity to become pro-inflammatory “ex-regulatory” T cells (exTregs). Because exTregs can subvert traditional regulatory T cells to exacerbate inflammation and contribute to pathologic autoimmune progression, there is great interest in understanding how and under what conditions exTregs develop. In preliminary work from our lab, we found that single cell RNA sequencing reveals extensive phenotypic heterogeneity of primary Tregs and exTregs from mouse gut, lungs, and lymph nodes. I propose using single cell genomics approaches to fully define the gene regulatory programs that govern exTreg development and polarization from destabilized Tregs. In my first aim, I will deeply analyze the single cell RNA sequencing data set to define the heterogeneity of exTreg phenotypes in distinct tissue microenvironments from which they were isolated. For my second aim, I will leverage my sponsors’ expertise in high-throughput genetic perturbation of primary mouse Tregs to perform a forward genetic screen to map the gene regulatory programs that maintain Treg identity and destabilize Tregs to exTregs induced by pro-inflammatory cytokines IL-4 or IL-6. My sponsor Alex Marson has extensive expertise in the genetics of immune cell function and autoimmunity, and in genetic engineering of primary T cells using CRISPR-Cas9. My co-sponsor Chun (Jimmie) Ye is a computational immunologist and human geneticist whose laboratory uses innovative technologies like single cell RNA sequencing to molecularly define processes of immune cell development and function. Additionally, I have secured scientific and career mentorship from renowned immunologists Dr. Jeffrey Bluestone (characterized exTregs in autoimmune inflammation) and Dr. Qizhi Tang (studies immune tolerance and autoimmunity). Concurrently, I am completing a longitudinal clinical preceptorship in pediatric immunology with Dr. Alice Chan, director of the UCSF Benioff Children’s Hospital Pediatric Immune Dysregulation Clinic and expert in genetic diagnosis of pediatric immune disorders. Overall, the proposed work will further our understanding of exTregs development and their role in autoimmune pathogenesis and progression. Moreover, this fellowship support will foster my training in immunology and computational biology, supporting me on my path through combined MD-PhD training towards a career as an academic pediatric immunologist studying the genetic bases of immune disorders.

项目总结/文摘