T helper cells in development of chronic inflammation and multimorbidity

T辅助细胞在慢性炎症和多发病发展中的作用

基本信息

批准号：
10737051
负责人：
JINGZHONG DING
金额：
$ 66.18万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737051
关键词：
Acceleration Adipose tissue Affect Aging Alzheimer&apos s Disease Animals Anti-Inflammatory Agents Autoimmune Biological Markers CREB1 gene Cardiovascular Diseases Cell Differentiation process Cells Chronic Chronic Disease Circulation Clinical Cryopreservation Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Diabetes Mellitus Dinoprostone Disease Elderly Genes Helper-Inducer T-Lymphocyte Human IL17 gene IL6 gene IgG Receptors Immune Immune response Immune system In Vitro Individual Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Intervention Literature Longitudinal Studies Macrophage Malignant Neoplasms Mediating Micro Array Data Microarray Analysis Multi-Ethnic Study of Atherosclerosis Mutation Organism Osteoporosis PTGS2 gene Participant Pathology Pathway interactions Peripheral Persons Phenotype Play Population Process Production Prostaglandin-Endoperoxide Synthase Prostaglandins Regulation Resources Risk Risk Reduction Role Sampling Signal Pathway Signal Transduction Specificity Testing Time Tissues Transcript Translations Work cardiovascular disorder risk circulating biomarkers cyclooxygenase 1 cytokine experimental study follow-up immune cell infiltrate improved indexing inflammatory marker monocyte mouse model multiple chronic conditions pharmacologic polarized cell prevent receptor single-cell RNA sequencing targeted treatment transcriptome sequencing

项目摘要

Multimorbidity, the coexistence of two or more chronic and often aging-related diseases, affects the majority of older adults. Chronic inflammation has been implicated in multimorbidity and individual aging-related diseases including cardiovascular disease, diabetes, cancer, Alzheimer’s disease, and osteoporosis. Anti-inflammatory therapy targeting IL1β reduces risk for cardiovascular disease, but clinical benefits of modulating inflammation remain controversial. Animal studies suggest that the infiltration of immune cells including T helper cells into the arterial wall, adipose, and other tissues may be the central mechanism underlying chronic inflammation and subsequent diseases. Most human studies, however, rely on inflammatory biomarkers such as IL6 and CRP, which lack mechanistic specificity. The paucity of human studies directly characterizing the immune cells’ role in the inflammatory process is a major gap retarding the translation of animal-based mechanistic work. We propose that T helper cells are an important contributor to both chronic inflammation and subsequent diseases because of their regulating immune response of both adaptive and innate immune cells including activation of monocytes/macrophages. This view is supported by our preliminary data from the Multi-Ethnic Study of Atherosclerosis (MESA) which shows the associations of pro-inflammatory signatures of T helper cells with multimorbidity, chronic inflammation, and inflammatory response of monocytes. While these microarray data support the role of T helper cells in chronic inflammation and multimorbidity, large longitudinal studies are needed to establish whether cellular features precede disease development. The proposed study will leverage the unique resource of isolated human T helper cells in MESA (N=1,900). We hypothesize that cellular features that coordinate the inflammatory response in peripheral T helper cells contribute to subsequent chronic inflammation, inflammatory changes in peripheral monocytes, and multimorbidity. To test this hypothesis, we will examine the following specific aims: 1) to examine whether omics profiles of T helper cells predict 11-year changes in multimorbidity in 1,900 MESA participants, 2) to evaluate whether omics profiles of T helper cells predict 6-year changes in omics profiles of monocytes and circulating pro-inflammatory biomarkers in 1,900 individuals, and 3) To test effects of pharmacological modulation of T helper cells from MESA participants on inflammatory responses. The proposed study will for the first time investigate the longitudinal relationship between omics profiles of T helper cells and multimorbidity in humans. The results from the proposed study will improve our understanding of inflammatory processes in humans, particularly their cellular features, and accelerate the development of more precisely targeted anti-inflammatory interventions for preventing multimorbidity.

多重发病，即两种或两种以上慢性且通常与衰老相关的疾病并存，影响着大多数人慢性炎症与多种疾病和个体衰老相关疾病有关。包括心血管疾病、糖尿病、癌症、阿尔茨海默病和骨质疏松症。针对 IL1 的治疗可降低心血管疾病的风险，但调节炎症的临床益处动物研究表明，包括 T 辅助细胞在内的免疫细胞的浸润仍然存在争议。动脉壁、脂肪和其他组织可能是慢性炎症的核心机制然而，大多数人类研究依赖于炎症生物标志物，例如 IL6 和 CRP，缺乏机制特异性，缺乏直接表征免疫细胞特征的人体研究。在炎症过程中的作用是阻碍基于动物的机制工作转化的一个主要差距。提出 T 辅助细胞是慢性炎症和后续疾病的重要贡献者因为它们调节适应性和先天免疫细胞的免疫反应，包括激活单核细胞/巨噬细胞的这一观点得到了我们多种族研究的初步数据的支持。动脉粥样硬化 (MESA) 显示 T 辅助细胞的促炎特征与动脉粥样硬化 (MESA) 的关联这些微阵列数据显示了单核细胞的多发病、慢性炎症和炎症反应。支持 T 辅助细胞在慢性炎症和多发病中的作用，大型纵向研究需要确定细胞特征是否先于疾病发展。拟议的研究将利用这一点。 MESA 中分离的人类 T 辅助细胞的独特资源 (N=1,900)。协调外周 T 辅助细胞炎症反应的特征有助于随后的治疗慢性炎症、外周单核细胞的炎症变化和多发病性来测试这一点。假设，我们将检查以下具体目标：1）检查 T 辅助细胞的组学特征是否预测 1,900 名 MESA 参与者的多发病 11 年变化，2) 评估组学概况是否 T辅助细胞预测单核细胞和循环促炎细胞组学特征的 6 年变化 1,900 名个体的生物标志物，以及 3) 测试 T 辅助细胞的药理调节效果 MESA 参与者对炎症反应的研究将首次进行调查。 T 辅助细胞组学特征与人类多发病之间的纵向关系。拟议研究中的结果将提高我们对人类炎症过程的理解，特别是他们的炎症过程细胞特征，并加速开发更精确的靶向抗炎干预措施预防多重疾病。