NLRP3 Inflammasome Activation and Mitochondrial Function in the setting of Aging and HIV Infection

衰老和 HIV 感染背景下 NLRP3 炎症小体激活和线粒体功能

• 批准号: 10190765
• 负责人: Heidi J Zapata
• 金额: $ 23.22万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190765
• 关键词: Acute-Phase Proteins; Address; Adipose tissue; Adult; Age; Aging; American; Atherosclerosis; Award; Biopsy; Blood; Blood Cells; Blood Coagulation Factor; CASP1 gene; Cardiovascular Diseases; Central obesity; Ceramides; Characteristics; Cholesterol; Chronic; Clinical; Communicable Diseases; Coupled; Crystallization; Cytometry; Data; Development; Development Plans; Diabetes Mellitus; Disease; Down-Regulation; Dyslipidemias; Elderly; Elements; Flow Cytometry; HIV; HIV Infections; HIV Seropositivity; Human; Hypertension; Immune; Immune system; Immunologic Receptors; Immunology; Individual; Inflammaging; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Insulin Resistance; Interleukin-18; Knowledge; Learning; Link; Liver; Mediating; Medical; Membrane Potentials; Mentorship; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolic syndrome; Metabolism; Methods; Mitochondria; Molecular; Multiprotein Complexes; Mus; Myeloid Cells; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Pattern; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Physicians; Play; Population; Production; Reactive Oxygen Species; Research; Role; Saturated Fatty Acids; Statistical Models; Testing; Training; Uric Acid; abdominal fat; age effect; age related; antiretroviral therapy; career; career development; cytokine; differential expression; human old age (65+); improved; inflammatory milieu; insulin sensitivity; insulin signaling; macrophage; marenostrin; medical schools; metabolic rate; mitochondrial dysfunction; monocyte; mouse model; pathogen; peripheral blood; protein complex; receptor; response; sensor; tool; transcriptome sequencing; transcriptomics; virology; young adult

Project Summary/Abstract: Both the aging and the aging HIV-infected population are characterized by increased rates of metabolic syndrome (defined by abdominal obesity, dyslipidemia, insulin resistance and hypertension). Notably, metabolic syndrome is associated with the dysregulated, age-associated pro-inflammatory environment— termed “Inflamm-aging”—characterized by elevated levels of cytokines, acute phase reactants, and clotting factors. Chronic stimulation of innate immune receptors by both pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) is thought to contribute to age-associated chronic inflammation, but the mechanisms underlying the pathogenesis of metabolic syndrome in the context of aging and HIV disease remain an incompletely understood knowledge gap in the field. The NLRP3 (NOD- like receptor pyrin domain-containing 3) inflammasome is an intracellular protein complex, that is part of the innate immune response and mediates the caspase-1-dependent cleavage of pro-IL-1b and pro-IL-18 to their activated forms. While the NLRP3 inflammasome is activated by PAMPs, there is increasing evidence for a role of NLRP3 as a sensor of host metabolism via DAMPs, as shown by NLRP3 activation by a wide range of metabolites. Moreover, NLRP3 inflammasome activation is dependent on mitochondrial function. The NLRP3 inflammasome has been linked to the development of insulin resistance and other metabolic syndromes in mouse models, and has been minimally explored in both older adults and HIV-infected adults. The purpose of this proposal is to determine the effects of age and HIV infection on the NLRP3 inflammasome, and its relationship with mitochondrial function by comparing the following groups of subjects, young adults (21-35), and older adults (≥ 60 yrs) with and without HIV-infection. Aim 1 seeks to characterize the NLRP3 inflammasome and its relationship with mitochondrial function, in myeloid cells from peripheral blood and adipose tissue. Aim 2 seeks to characterize the metabolic pathways that are induced with activation of the NLRP3 inflammasome through RNA sequencing and CyTOF in myeloid cells from peripheral blood and adipose tissue. Data from both aims will be collected in conjunction with clinical characteristics including the components of metabolic syndrome. Our hypothesis is that increased age and HIV infection will result in dysregulated NLRP3 inflammasome function at baseline and with activation that is linked to mitochondrial dysfunction—ultimately contributing to the development of metabolic syndrome in older and HIV-infected adults. The candidate, Dr. Zapata is an Infectious Disease physician at the Yale school of medicine, who has put together an interdisciplinary mentorship committee with expertise in immunology, aging, and metabolism. This training proposal is coupled with a career development plan that includes mentorship and didactic training in Immuno-metabolism, with an additional focus on learning the analysis of sequencing data, thus providing the tools that will allow the PI to apply for an R01 award.

项目摘要/摘要： 衰老和感染HIV的衰老人群的特征是代谢率提高 综合征（由腹部肥胖，血脂异常，胰岛素抵抗和高血压定义）。尤其， 代谢综合征与失调的，与年龄相关的促炎环境 - 被称为“炎症” - 由细胞因子水平升高，急性相应物和衣服表征 因素。通过两种病原体相关的分子模式，长期刺激先天免疫受体 （PAMP）和损害相关的分子模式（抑制）被认为有助于与年龄相关 慢性炎症，但是在这种情况下代谢综合征发病机理的基础机制 衰老和艾滋病毒疾病仍然是该领域的知识差距。 nlrp3（点头 - 像受体吡啶结构域3）炎性体是一种细胞内蛋白质复合物，是该蛋白的一部分 先天免疫反应并介导pro-il-1b和pro-il-18的caspase-1依赖性裂解 激活形式。虽然NLRP3炎性小体被大型弹药激活，但有越来越多的证据表明 NLRP3作为宿主代谢传感器的作用，通过潮湿，如NLRP3激活所示 代谢物。此外，NLRP3炎性体激活取决于线粒体功能。 NLRP3 炎性体与胰岛素抵抗和其他代谢综合征的发展有关 小鼠模型，并且在老年人和HIV感染的成年人中都经过最低限度的探索。目的 该建议是确定年龄和艾滋病毒感染对NLRP3炎症体的影响，及其 通过比较以下受试者，年轻人（21-35），与线粒体功能的关系， 以及有和没有HIV感染的老年人（≥60岁）。 AIM 1试图表征NLRP3 炎性体及其与线粒体功能的关系，外周血和 脂肪组织。 AIM 2试图表征被激活引起的代谢途径 NLRP3炎性体通过RNA测序和细胞中的髓样细胞中的细胞和细胞，来自外周血和 脂肪组织。来自两个目标的数据将与临床特征一起收集 代谢综合征的成分。我们的假设是，年龄增加和HIV感染将导致 基线时的NLRP3炎性体功能失调，并且与激活有关 线粒体功能障碍 - 在老年和 艾滋病毒感染的成年人。候选人Zapata博士是耶鲁学校的传染病医师 Medicine，他组成了一个跨学科心态委员会，具有免疫学，衰老， 和新陈代谢。该培训建议与包括MentalShip在内的职业发展计划相结合 以及免疫代谢中的教学培训，额外的重点是学习测序分析 数据，因此提供了将允许PI申请R01奖励的工具。