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：
10689271
负责人：
Ellen R Richie
金额：
$ 280.03万
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/10689271
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 Collaborations Communicable Diseases Communication Programs Complement Complex Cytoprotection Data Data Set Dendritic Cells Development Emigrations Environment Epithelial Cell Proliferation Gene Expression Profile Gene Expression Profiling Generations Genetic Transcription Goals Growth Hematopoietic Homeostasis Human Image Immune Immune Tolerance Immune response Knowledge Leadership Life Location Macrophage Maps Mediating Molecular Molecular Analysis Mus Nature Neonatal Newborn Infant Outcomes Research Output Pathway interactions Patients Perinatal Phase Phenotype Play Population Process Proliferating 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 Visualization autoreactive T cell candidate identification cell type central tolerance congenital immunodeficiency experimental study immune function immune self tolerance multiplexed imaging neonatal health novel pathogen perinatal period phenotypic data postnatal programs rapid growth reconstitution restraint retinoblastoma pathway single-cell RNA sequencing synergism 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

概括该程序提案的综合假设是与年龄相关的细胞和分子特征小鼠百里胸微环境的相似特征在人胸中的相似特征中，在在围产期与少年时期。当前，关于老鼠的信息，甚至在人类中甚至更少的信息，关于变化的信息胸腺上皮细胞（TEC），造血抗原呈递细胞（HAPC）的组成和功能和功能在此过渡期间，其他基质细胞子集。鉴于具有效应子和调节功能的T细胞至关重要对于新生儿健康，计划研究目标是：1）确定组成的变化和两只小鼠的围产期围产期过渡到围产期的TEC，HAPC和其他胸腺基质细胞的组织和人类； 2）在调节其增殖的这些细胞子集中的地图转录变化，分化，功能和串扰； 3）确定这种变化如何影响围产期的能力胸腺环境产生具有不同功能能力的T细胞。该程序的结构是使用SCRNA-SEQ和多重成像来协作识别候选单元小鼠和人胸部功能上重大变化的种群和分子机制微环境跨越幼年过渡。在发现阶段，RPS将产生SCRNA- TECS（RP1），基质细胞（RP2）和HAPC（RP3）的SEQ数据集，来自小鼠和人（核心C）胸腺。这些数据集将通过核心B分析，以鉴定细胞和分子候选物。在优先级阶段，RPS将确定哪些候选物在具有核心B的物种中保存。使用多重成像来可视化在这些候选人期间这些候选者的位置和/或相互作用的变化可能介导重要生物学功能的过渡。物种保护和成像结果将提供一个基本原理，以优先考虑细胞子集和用于功能测试的分子途径。在测试阶段，每个RP将评估新颖以及先前确定的候选者，以根据功能意义项目特定目标。总的来说，这些RPS中的这些平行的SCRNA-seq和成像实验将协同为：1）确定转录曲线的变化，细胞组成和组织的变化在小鼠和人类的幼年过渡到幼年过渡的胸腺微环境； 2）使我们能够测试哪些改变调节这些子集的增殖，分化和功能下游对围产期免疫功能的后果。程序组件是： RP1（Richie）：控制TEC动力学和谱系层次结构的分子机制 RP2（Manley）：FOXN1在控制从胸腺扩张到体内平衡的过渡中的作用 RP3（Ehrlich）：胸腺对成人过渡期间胸腺APC对中央公差的差异贡献核心A（Richie）：管理员。核;核心B（Yi）：生物信息学/生物稳定核心；核心C ：（ Hale）人百里核心