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

• 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
• 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' 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

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.

多发病，即两种或两种以上慢性疾病的共存，通常与衰老有关，影响大多数 上了年纪的人。慢性炎症与多发病和个体衰老相关疾病有关 包括心血管疾病、糖尿病、癌症、老年痴呆症和骨质疏松症。抗炎 针对IL1β的治疗降低了心血管疾病的风险，但调节炎症的临床好处 仍然存在争议。动物研究表明，包括T辅助细胞在内的免疫细胞渗透到 动脉壁、脂肪和其他组织可能是慢性炎症的中心机制。 以及随后的疾病。然而，大多数人类研究依赖于炎性生物标记物，如IL6和 C反应蛋白缺乏机械性特异性。缺乏直接描述免疫细胞特征的人类研究 炎症过程中的作用是一大缺口，延缓了动物基础机械工作的转化。我们 提出辅助性T细胞是慢性炎症和后续疾病的重要因素 因为它们调节适应性免疫细胞和先天免疫细胞的免疫反应，包括激活 单核/巨噬细胞。这一观点得到了我们来自多种族研究的初步数据的支持 动脉粥样硬化(MESA)，显示辅助性T细胞的促炎信号与 单核细胞的多发病、慢性炎症和炎症反应。虽然这些微阵列数据 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的发展。拟议的研究将利用 梅萨地区分离的人类辅助性T细胞的唯一来源(N=1900)。我们假设细胞 协调外周T辅助细胞炎症反应的功能有助于随后 慢性炎症、外周血单核细胞炎性改变和多发病。为了测试这一点 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 预测1900名MESA参与者11年来多病发病率的变化，2)评估组学特征 辅助性T细胞预测单核细胞和循环促炎因子组学的6年变化 1900个个体的生物标记物，以及3)测试药物对来自 梅萨与会者对炎症反应的看法。拟议的研究将首次调查 人类辅助性T细胞组学特征与多发病的纵向关系。结果是 这项拟议的研究将提高我们对人类炎症过程的理解，特别是他们 细胞特征，并加快开发更精确的针对性抗炎干预措施 预防多发病。