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: 10596129
• 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/10596129
• 关键词: Adult; Advisory Committees; Affect; Age; Aging; Antigens; Biology of Aging; Cell Compartmentation; Cell Survival; Cells; Cellular Immunity; Cellular biology; Clinical; Communicable Diseases; Communities; Data; Development; Development Plans; Doctor of Philosophy; Educational workshop; Elderly; Emigrant; Ensure; Environment; Epithelium; 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; Institution; Interleukin-13; Investigation; K-Series Research Career Programs; Licensing; Life; Link; Longevity; LoxP-flanked allele; Mediator; Mentors; Mentorship; Mesenchymal; Mesenchyme; Metabolic; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Nature; Output; Pathway interactions; Peripheral; Production; Productivity; Proteins; Publications; Research; Research Institute; Research Proposals; Residencies; Role; Shapes; Signal Transduction; Sorting; 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; Vaccination; Work; Youth; aged; arginase; career; career development; cytokine; emerging adult; eosinophil; epigenome; genome-wide; immune restorative treatment; 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.

程序摘要/摘要 老年人中的T细胞介导的不良免疫与病态增加和死亡率有关 逐渐减弱的免疫力正在逐渐减弱。 部分归因于胸腺功能的变化，从生命的头十年开始，并发展为胸腺 然而，在成年早期至中期 在早期生命中有组织和功能性胸腺环境，胸腺衰老期间的变化 修改幼稚的t角色是众所周知的。 髓质胸腺功能和功能障碍，在衰老期间包含的机制以及如何 状态塑造幼稚的T细胞发育，目的是为新型的免疫治疗疗法提供信息。 他对Stromal-rmmune crostalk Stark的兴趣从博士研究开始，当时他是MD/PhD学员的兴趣，他在那里开始 T细胞存活细胞因子的外围来源，IL-7。 放弃居住权，有利于博士后培训，并专注于上皮的异质性 胸腺髓质，导致了自然的第一作者出版物。 培训是基于他渴望利用他在Stromal-imune crostalk上的专业知识来过渡城镇 系统方法了解胸膜胸腔和幼稚的T细胞在整个生命中的发展。 这项研究建议着重于胸腺上皮的令人惊讶的作用 由造血限制的细胞因子建立，极化和支持髓质的基质环境。 我们的初步数据揭示了胸腺上皮作为IL-13的意外来源。 哪些IL-13从胸皮上皮有选择地删除，我们对挖掘是对上皮的影响 和间充质，髓样细胞以及间接的，幼稚的t -cell特征，从而建立了一个框架 了解近代环境的变化如何形成幼稚的T细胞特征。 米勒博士已经为一项为期5年的职业发展计划提供了，在此期间他将通过 马克·安德森（Mark Anderson）博士及其咨询委员会，其中包括一群精心策划的科学领袖 具有T -Cell生物学，2型细胞因子和衰老生物学的专业知识。 出勤和讲习班将使他能够实现新的技术扩展他的知识基础基础基础 在衰老生物学领域的科学网络。 无与伦比的基本免疫学和科学职业发展的机构。 Buck CEO埃里克·韦丁（Eric Verdin）的老龄化和英语研究所的接近 将确保米勒博士在老化生物学社区内的科学和专业人士。 在Theiserer Development奖的压缩中，D。Miller将培养技术技能和 特定于领域的专业知识，以启动胸腺稳态和衰老的独立研究计划。