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

• 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
• 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

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 该计划提案的综合假设是，与年龄相关的细胞和分子特征 小鼠胸腺微环境的变化与人类胸腺的相似特征相似，在 塑造围产期和孕期从胸腺迁移的 T 细胞的独特功能潜力 少年时期。目前，关于小鼠的信息很少，关于人类的信息则更少。 胸腺上皮细胞（TEC）、造血抗原呈递细胞（HAPC）的组成和功能，以及 在此转变期间的其他基质细胞亚群。鉴于具有效应和调节功能的 T 细胞至关重要 对于新生儿健康，该计划的研究目标是：1）确定成分和成分的变化 两只小鼠从围产期到幼年期过渡期间 TEC、HAPC 和其他胸腺基质细胞的组织 和人类； 2）绘制这些细胞亚群中调节其增殖的转录变化， 差异化、功能和串扰； 3) 确定这些变化如何影响围产期的能力 胸腺环境产生具有独特功能的 T 细胞。 该计划的结构是使用 scRNA-seq 和多重成像来协作识别候选细胞 小鼠和人类胸腺功能显着变化的群体和分子机制 整个围产期到青少年过渡的微环境。在发现阶段，RP 将生成 scRNA- 来自小鼠和人类 (Core C) 胸腺的 TEC (RP1)、基质细胞 (RP2) 和 HAPC (RP3) 的 seq 数据集。 Core B 将分析这些数据集，以确定细胞和分子候选者。在优先级排序中 阶段，RP 将确定哪些候选者与 Core B 跨物种保守。然后 RP 将进行合作 使用多重成像来可视化这些候选者在检测过程中位置和/或相互作用的变化 可能介导重要生物学功能的转变。物种保护和成像结果都将 为功能测试的细胞亚群和分子途径的优先顺序提供基本原理。在测试阶段， 每个 RP 将根据以下标准评估新颖的以及先前确定的候选者的功能意义 项目具体目标。总的来说，三个 RP 中的这些并行 scRNA-seq 和成像实验将 协同作用：1）识别转录谱、细胞组成和组织的变化 小鼠和人类从围产期到幼年过渡期间的胸腺微环境； 2) 使我们能够 测试哪些变化在过渡过程中调节这些子集的增殖、分化和功能 对围产期免疫功能的下游影响。程序组成部分是： RP1 (Richie)：控制围产期胸腺中 TEC 动力学和谱系层次结构的分子机制 RP2 (Manley)：Foxn1 在控制胸腺扩张到稳态转变中的作用 RP3 (Ehrlich)：胸腺 APC 在围产期到成人过渡期间对中枢耐受的不同贡献 核心A（Richie）：管理员。核;核心B（Yi）：生物信息学/生物统计学核心；核心C：（硬朗）人类胸腺核心