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Mechanisms controlling distinct growth and functional characteristics of the perinatal and adult thymus

控制围产期和成人胸腺不同生长和功能特征的机制

基本信息

批准号：
10251293
负责人：
Ellen R Richie
金额：
$ 230.62万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10251293
关键词：
Adolescent Adult Affect Age Antigen-Presenting Cells Autoimmune Autoimmunity B-Lymphocytes Bioinformatics Biological Process Biology Biometry Birth Cell Compartmentation Cell Differentiation process Cell Proliferation Cell physiology Cells Cellular biology Cellularity Characteristics Communicable Diseases Communication Programs Complement Complex Data Data Set Dendritic Cells Development Environment Epithelial Cell Proliferation Gene Expression Profile Gene Expression Profiling Generations Genetic Transcription Goals Growth Hematopoietic Homeostasis Human Image Immune Immune response Immune system Knowledge Leadership Life Location Maps Mediating Molecular Molecular Analysis Mus Nature Neonatal Newborn Infant Outcomes Research Output Pathway interactions Patients Perinatal Phase Phenotype Play Population Process Property Publishing Regulatory T-Lymphocyte Reporting Research Research Project Grants Retinoblastoma Role Self Tolerance Shapes Stromal Cells Structure T-Cell Development T-Lymphocyte Testing Thymic epithelial cell Thymus Gland Time autoreactive T cell cell type central tolerance congenital immunodeficiency experimental study immune function immune self tolerance macrophage multiplexed imaging neonatal health novel pathogen perinatal period phenotypic data postnatal programs rapid growth reconstitution retinoblastoma pathway single-cell RNA sequencing transcription factor transcriptome sequencing

项目摘要

Summary The integrated hypothesis of this Program proposal is that age-associated cellular and molecular features of the mouse thymus microenvironment, mirrored by similar features in the human thymus, play a major role in shaping the distinct functional potential of T cells that emigrate from the thymus during the perinatal versus juvenile periods. Currently, there is little information in mice, and even less in humans, on changes in the composition and function of thymic epithelial cells (TECs), hematopoietic antigen presenting cells (HAPCs), and other stromal cell subsets during this transition. Given that T cells with effector and regulatory functions are vital for newborn health, the Program research objectives are to: 1) identify changes in the composition and organization of TECs, HAPCs and other thymus stromal cells over the perinatal to juvenile transition in both mice and humans; 2) map transcriptional changes in these cellular subsets that regulate their proliferation, differentiation, function and cross-talk; and 3) determine how such changes impact the ability of the perinatal thymic environment to generate T cells with distinct functional capabilities. The Program is structured to use scRNA-seq and multiplex imaging to collaboratively identify candidate cell populations and molecular mechanisms underlying functionally significant changes in mouse and human thymus microenvironments across the perinatal to juvenile transition. In the discovery phase, RPs will generate scRNA- seq datasets of TECs (RP1), stromal cells (RP2) and HAPCs (RP3) from mouse and human (Core C) thymus. These datasets will be analyzed by Core B to identify cellular and molecular candidates. In the prioritization phase, RPs will determine which candidates are conserved across species with Core B. RPs will then collaborate to use multiplex imaging to visualize changes in location and/or interactions of these candidates during the transition that may mediate important biological functions. Both species conservation and imaging results will provide a rationale to prioritize cell subsets and molecular pathways for functional testing. In the testing phase, each RP will assess novel, as well as previously identified candidates, for functional significance according to Project specific goals. Collectively, these parallel scRNA-seq and imaging experiments in the three RPs will synergize to: 1) identify changes in the transcriptional profiles, cellular composition and organization of the thymus microenvironment over the perinatal to juvenile transition in both mice and humans; and 2) enable us to test which changes regulate proliferation, differentiation, and function of these subsets across the transition with downstream consequences for perinatal immune function. Program components are: RP1 (Richie): Molecular mechanisms controlling TEC dynamics and lineage hierarchies in the perinatal thymus RP2 (Manley): The role of Foxn1 in controlling the transition from thymus expansion to homeostasis RP3 (Ehrlich): Differential contribution of thymic APCs to central tolerance during the perinatal to adult transition Core A (Richie): Admin. Core; Core B (Yi): Bioinformatics/Biostats Core; Core C: (Hale) Human Thymus Core