Dysregulation of Naïve T cell Quiescence during Aging

衰老过程中幼稚 T 细胞静止的失调

基本信息

批准号：
10456507
负责人：
Claire Gustafson
金额：
$ 10.64万
依托单位：
ALLEN INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-26 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456507
关键词：
Adenosine Age Aging Antigens Area Biological Assay Biological Models Biomedical Engineering Cell Aging Cell Compartmentation Cell Differentiation process Cell Maintenance Cell Survival Cell physiology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cellular biology Cytometry Data Data Set Development Plans Encapsulated Environment Epigenetic Process Flow Cytometry Functional disorder Genetic Transcription Goals Heterogeneity Homeostasis Human IL7 gene Immune Immune response Immunity In Vitro Incidence Individual Infection Intervention Knowledge Light Link Longitudinal Studies Lymphoid Lymphoid Tissue Maintenance Mediating Mediator of activation protein Memory Mentors Mentorship Methodology Organoids Pathogenicity Pathway interactions Phenotype Play Population Population Heterogeneity Predisposition Problem Solving Production Property Prostaglandins RNA Reproducibility Research Research Personnel Resources Reticular Cell Role Signal Transduction Stromal Cells System T-Lymphocyte Techniques Therapeutic Intervention Time Tissues Universities Work XCL1 gene age related aged analysis pipeline base career development cytokine functional loss healthspan humanized mouse immune function improved in vitro Assay innovation insight middle age mortality mouse model novel peripheral blood prevent research and development single cell technology stem technique development

项目摘要

Project Summary/Abstract A common feature of human aging is an increased susceptibility to infections. This age-related susceptibility is linked with a significant and reproducible loss of naïve T cells in older individuals. Notably, aged naïve cells not only reduce in number but also display features of partial differentiation, implying a loss in cellular quiescence may cause repertoire contraction and dysfunction with age. Naïve T cell quiescence is classically maintained within secondary lymphoid tissues (SLTs) by fibroblastic reticular cells (FRCs). Mouse models have elegantly demonstrated the ability of FRCs to promote T cell survival and directly inhibit activation-induced differentiation. These data suggest that FRCs actively regulate naïve T cell quiescence and likely play an essential role in its loss during aging. However, mechanistic studies in humans are significantly confounded by rare use of single cell technologies and limited by poor naïve T cell survival in standard in vitro culture and humanized mice. Better utilization of new single cell techniques and the development of novel methodologies that sustain naïve T cells in vitro is thus required to gain further insight into naïve T cell maintenance during human aging. Our preliminary data suggests high heterogeneity of human naïve T cells that narrows with age, a situation that can be mimicked in vitro through the use of a novel SLT-like organoid model system. For this proposal, Aim 1 will define the overall phenotypic, transcriptional and epigenetic heterogeneity of the naïve T cell compartment during human aging. In addition, Aim 2 will further develop SLT-like organoids for the long- term study of naïve T cell quiescence. Aim 3 will use our organoid system, in combination with ex vivo and in vitro assays, to determine the role of FRCs in the maintenance of naïve T cell quiescence and its breakdown with aging. The overarching goals of these studies are to define fundamental naïve T cell heterogeneity and determine causes of age-related homeostatic decline – to ultimately identify potential therapeutic interventions to boost protective immunity and prevent pathogenic infections in older individuals. The applicant Dr. Claire Gustafson has outlined an integrative five-year research and career development plan to advance her knowledge in single cell techniques and their analysis pipelines and to develop a novel, organoid-based research platform to study T cell homeostasis during aging. Dr. Gustafson’s mentor, Dr. Jörg Goronzy, has comprehensive expertise in T cell aging as well as an extensive network of scientific collaborators using high throughput analytical techniques. This mentorship combined with Dr. Gustafson’s team of expert advisors and the resources available at Stanford University provides an exceptional research environment for Dr. Gustafson to successfully become a strong independent investigator in the area of human immune aging.

项目概要/摘要人类衰老的一个共同特征是对感染的易感性增加，这种与年龄相关的易感性是。与老年个体中幼稚 T 细胞的显着且可重复的损失有关，值得注意的是，衰老的幼稚细胞则不然。不仅数量减少，而且还表现出部分分化的特征，这意味着细胞静止的丧失随着年龄的增长，幼稚 T 细胞通常会保持静止状态，从而导致功能收缩和功能障碍。小鼠模型中的成纤维细胞网状细胞（FRC）在次级淋巴组织（SLT）中具有优雅的作用。 FRC 促进 T 细胞存活并直接抑制激活诱导的能力这些数据表明 FRC 积极调节幼稚 T 细胞静止并可能发挥重要作用。然而，人类的机制研究却受到了严重的干扰。单细胞技术的使用很少，并且受到标准体外培养中幼稚 T 细胞存活率较差的限制，人源化小鼠。更好地利用新的单细胞技术和新方法的开发。因此，需要在体外维持幼稚 T 细胞，以进一步了解幼稚 T 细胞在我们的初步数据表明人类初始 T 细胞的高度异质性随着年龄的增长而缩小，可以通过使用新型 SLT 类器官模型系统在体外模拟这种情况。提案中，目标 1 将定义幼稚 T 的整体表型、转录和表观遗传异质性此外，Aim 2 将进一步开发类似 SLT 的类器官，用于长期研究。目标 3 将使用我们的类器官系统，结合离体和体内研究。体外测定，以确定 FRC 在维持初始 T 细胞静止及其分解中的作用这些研究的首要目标是确定基本的初始 T 细胞异质性和确定与年龄相关的稳态下降的原因——最终确定潜在的治疗干预措施增强老年人的保护性免疫力并预防病原体感染。古斯塔夫森概述了一个综合的五年研究和职业发展计划，以推动她的发展单细胞技术及其分析流程的知识，并开发一种新颖的、基于类器官的 Gustafson 博士的导师 Jörg Goronzy 博士建立了研究衰老过程中 T 细胞稳态的研究平台。 T 细胞衰老方面的全面专业知识以及使用高技术的广泛科学合作者网络吞吐量分析技术由 Gustafson 博士的专家顾问团队共同指导。斯坦福大学的资源为古斯塔夫森博士提供了卓越的研究环境成功成为人类免疫衰老领域强有力的独立研究者。