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Project 1 - Goldrath

项目1-戈德拉思

基本信息

批准号：
10453791
负责人：
Ananda W Goldrath
金额：
$ 49.44万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-17 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453791
关键词：
Acute Adopted Adoptive Transfer Affect Antigens Automobile Driving Blood Body Surface CD8-Positive T-Lymphocytes Cell Differentiation process Cell division Cells Cellular biology ChIP-seq Chronic Communicable Diseases Data Dependence Development E protein Effector Cell Enhancers Epigenetic Process Equilibrium Event Exhibits FOXO1A gene FOXO3A gene Gene Expression Gene Expression Profiling Generations Genes Genetic Transcription Genomics Goals Heterogeneity Homeostasis Hybrids ID2 gene Immune Immunologic Memory Impairment Individual Infection Inflammation Inhibitor of Differentiation Proteins Literature Lymphoid Tissue Maintenance Malignant Neoplasms Mediating Memory Messenger RNA Metabolic Pathway Modeling Molecular Neoplasm Metastasis Pathway interactions Phenotype Population Proteins Regulatory Element Reporter Role Sentinel T cell differentiation T memory cell T-Lymphocyte Testing Tissue Differentiation Tissues Transcription Repressor Vital capacity acute infection base cell fate specification chronic infection first responder immunopathology improved in vivo inhibitor intestinal epithelium novel vaccines programs rational design recruit residence response screening single cell analysis single-cell RNA sequencing small hairpin RNA transcription factor tumor growth

项目摘要

SUMMARY-PROJECT 1-GOLDRATH: Long-lived memory cells provide protection from reinfection and can serve as endogenous defenders against tumor growth and metastases. Tissue-resident memory T cells provide essential sentinel protection at body surfaces such as the intestinal epithelium, and are now clearly understood to be among the key `first responders' in many infection settings. Although we know that resident-memory cells are an essential component of immune memory, little is known about the transcriptional pathways regulating their formation, survival and function. Improving our understanding of these topics will allow us to harness the immediate protective capacity of this vital memory T cell population and modulate their activity in the context of immunopathology, which is the overarching goal of the Program Project. Benefiting from the combined expertise in cutting-edge epigenetic and genomic analyses, CD8+ T cell biology, and chronic infection of the Program Project and Core Leaders, Project 1 will define the relationship of transcriptional programs driving unique memory states with a focus on resident versus circulating memory populations. The heterogeneity, gene-expression programs, functional activity and regulatory elements involved in resident- memory cell development will be studied to generate an integrated understanding of how transcriptional regulators such as Blimp1, Bcl6, T-bet, and E/Id proteins drive divergent differentiation programs in memory cell precursors to promote differentiation of distinct memory fates. To this end, specifically, we will: (1) Define the relationship of transcriptional programs driving unique memory states to understand how resident-memory T cell differentiation diverges from circulating memory T cell populations. Single-cell analysis of gene expression will be paired with high-throughput functional screening to assess the hybrid transcriptional network regulating the formation and homeostasis of Trm populations. (2) Decipher the contradictory dependence of Trm on the antagonistic transcriptional repressors, Blimp1 and Bcl6 in Trm differentiation and homeostasis. (3) Resolve the role of E protein transcription factors and their regulators in the transcriptional network governing the development, function and homeostasis of tissue-resident memory T cells in acute and chronic infectious settings. Our studies identifying key molecular determinants and transcriptional programs that control resident- memory T cell fate specification are critical to inform the rational design of the next generation of vaccines that will specifically aim to invoke tissue-resident memory cell-mediated protection from infectious diseases and malignancy. !

SUMMARY-PROJECT 1-GOLDRATH: