Mechanisms of thymic stromal-immune crosstalk for homeostasis and naïve T cell licensing across life

胸腺基质-免疫串扰在生命过程中维持稳态和幼稚 T 细胞许可的机制

• 批准号: 10388384
• 负责人: Corey Nicholas Miller
• 金额: $ 14.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388384
• 关键词: Adult; Advisory Committees; Affect; Age; Aging; Antigens; Biology of Aging; Cell Compartmentation; Cell Survival; Cells; Cellular Immunity; Cellular biology; Climacteric; Clinical; Communicable Diseases; Communities; Data; Development; Development Plans; Doctor of Philosophy; Educational workshop; Elderly; Emigrant; Ensure; Environment; Epithelial; Flow Cytometry; Foundations; Frequencies; Functional disorder; Future; Goals; Growth; Hematopoietic; Heterogeneity; Homeostasis; Host Defense; Human; IL7 gene; ITGAM gene; ITGAX gene; Immune; Immunity; Immunofluorescence Immunologic; Immunology; Interleukin-13; Investigation; K-Series Research Career Programs; Licensing; Life; Link; Longevity; Mediator of activation protein; Mentors; Mentorship; Mesenchymal; Mesenchyme; Metabolic; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Nature; Output; Pathway interactions; Peripheral; Production; Proteins; Publications; Research; Research Institute; Research Proposals; Residencies; Role; Shapes; Signal Transduction; Source; Stains; Stromal Cells; Structure of thymic medulla; System; T-Cell Development; T-Lymphocyte; Technical Expertise; Thymic epithelial cell; Thymocyte Development; Thymus Gland; Tissues; Training; Tumor Immunity; Tumor stage; Vaccination; Work; Youth; aged; arginase; base; career; career development; cytokine; emerging adult; eosinophil; epigenome; genome-wide; imprint; interest; interleukin-13 receptor; knowledge base; medical schools; mortality; mouse model; novel; polarized cell; post-doctoral training; programs; response; single-cell RNA sequencing; symposium; thymocyte; verdin photosensitizer; young adult

PROGRAM SUMMARY/ABSTRACT Poor T cell mediated immunity in the elderly is associated with increased morbidity and mortality from infectious diseases, suboptimal cancer immunity, and poor responses to vaccination. Waning T cell immunity is due in part to changes in thymic function beginning in the first decade of life and progressing to thymic involution in early to middle adulthood. However, how stromal-immune crosstalk maintains a differentiated, organized, and functional thymic stromal environment during early life, changes during thymic aging, and modifies naïve T cell character is poorly understood. Dr. Corey Miller’s career focus is to understand the mechanisms underlying medullary thymic function and dysfunction, including during aging, and how these states shape naïve T cell development, with the goal of informing novel immunorestorative therapies. His interest in stromal-immune crosstalk started during his doctoral research as an MD/PhD trainee, where he investigated peripheral sources of the T cell survival cytokine, IL-7. After completing medical school, he chose to forgo residency in favor of postdoctoral training and has focused on epithelial heterogeneity within the thymic medulla, leading to a first author publication in Nature. Dr. Miller’s pursuit of further career development training is based on his desire to leverage his expertise in stromal-immune crosstalk to transition towards a systems approach to understanding thymic homeostasis and naïve T cell development across life. This research proposal focuses on a surprising role for the thymic epithelium in expressing a hematopoietically-restricted cytokine to establish, polarize, and support the medullary stromal environment. Our preliminary data reveal the thymic epithelium as an unexpected source of IL-13. Using a mouse model in which IL-13 is selectively deleted from thymic epithelium, we propose aims to dissect its effects on epithelium and mesenchyme, myeloid cells, and, indirectly, naïve T cell character—thereby establishing a framework for understanding how changes in the medullary environment shape naïve T cell character. Dr. Miller has proposed a 5-year career development plan during which he will have direct mentorship by Dr. Mark Anderson and his advisory committee, which includes a carefully curated group of scientific leaders with expertise in T cell biology, type 2 cytokines, and aging biology. His proposed coursework, conference attendance and workshops will enable him to achieve new technical expertise and expand his knowledge base and scientific network in the field of aging biology. This training period will be spent at UCSF, which is an unrivaled institutional environment for basic immunology and scientific career development. In addition, proximity to the Buck Institute for Research on Aging and engagement of Buck CEO, Eric Verdin, as a mentor will ensure Dr. Miller’s scientific and professional growth within the aging biology community. At the completion of this career development award, Dr. Miller will have cultivated the technical skills and domain-specific expertise to launch an independent research program in thymic homeostasis and aging.

项目概要/摘要 老年人 T 细胞介导的免疫力较差与以下疾病的发病率和死亡率增加有关： 传染病、癌症免疫力不佳以及 T 细胞免疫力下降。 部分原因是胸腺功能的变化从生命的第一个十年开始并进展为胸腺 然而，基质免疫串扰如何维持分化的、 生命早期有组织的、功能性的胸腺基质环境，胸腺衰老过程中的变化，以及 人们对改变幼稚 T 细胞特性知之甚少。科里·米勒 (Corey Miller) 博士的职业重点是了解 胸腺髓质功能和功能障碍的潜在机制，包括衰老过程中的机制，以及这些机制如何 状态塑造了幼稚 T 细胞的发育，目的是为新型免疫恢复疗法提供信息。 他对基质免疫串扰的兴趣始于他作为医学博士/博士生的博士研究期间，在那里他 完成医学院学业后，他选择了研究 T 细胞存活细胞因子 IL-7 的外周来源。 放弃住院医师培训，转而接受博士后培训，并专注于研究内皮细胞的异质性 胸腺髓质，导致米勒博士在《自然》杂志上发表第一作者论文，追求进一步的职业发展。 培训是基于他希望利用他在基质免疫串扰方面的专业知识来过渡到 系统方法来了解胸腺稳态和一生中幼稚 T 细胞的发育。 这项研究计划的重点是胸腺上皮在表达 造血限制性细胞因子，用于建立、极化和支持髓质基质环境。 我们的初步数据显示，胸腺上皮是 IL-13 的意外来源。 其中IL-13被选择性地从胸腺上皮中删除，我们提出的目的是剖析其对上皮的影响 和间充质、骨髓细胞，以及间接的幼稚 T 细胞特征，从而建立了一个框架 了解髓质环境的变化如何塑造幼稚 T 细胞的特性。 米勒博士提出了一个为期 5 年的职业发展计划，在此期间他将得到以下人员的直接指导： 马克·安德森博士和他的顾问委员会，其中包括精心策划的科学领导小组 拥有 T 细胞生物学、2 型细胞因子和衰老生物学方面的专业知识。他提议的课程、会议。 出席和参加研讨会将使他能够获得新的技术专业知识并扩大他的知识库 本次培训将在加州大学旧金山分校 (UCSF) 度过，这是一个衰老生物学领域的科学网络。 此外，为基础免疫学和科学职业发展提供无与伦比的制度环境。 毗邻巴克衰老研究所，并由巴克首席执行官埃里克·维尔丁 (Eric Verdin) 担任导师 将确保米勒博士在衰老生物学界的科学和专业发展。 完成此职业发展奖后，米勒博士将培养技术技能和 特定领域的专业知识启动胸腺稳态和衰老的独立研究计划。