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: 10680480
• 负责人: Heidi J Zapata
• 金额: $ 22.07万
• 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/10680480
• 关键词: Acute-Phase Proteins; 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; Color; Communicable Diseases; Coupled; Cytometry; Data; Development; Development Plans; Diabetes Mellitus; Disease; Down-Regulation; Dyslipidemias; Elderly; Elements; Flow Cytometry; HIV; HIV Infections; HIV Seropositivity; Human; Hypertension; IL18 gene; Immune; Immune system; Immunologic Receptors; Immunology; Individual; Inflammaging; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Insulin Resistance; Knowledge; Learning; Link; Liver; Macrophage; 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; marenostrin; medical schools; metabolic rate; mitochondrial dysfunction; monocyte; mouse model; pathogen; peripheral blood; protein complex; receptor; response; sensor; tool; transcriptome sequencing; transcriptomics; 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.

项目概要/摘要： 老龄化和老龄化的艾滋病毒感染人口的特点是代谢率增加， 综合征（定义为腹部肥胖、血脂异常、胰岛素抵抗和高血压）。值得注意的是， 代谢综合征与失调、年龄相关的促炎环境有关， 称为"炎症-老化"-特征为细胞因子、急性期反应物和凝血水平升高 因素两种病原体相关分子模式对先天免疫受体的慢性刺激 PAMPs和损伤相关分子模式（DAMPs）被认为有助于与年龄相关的 慢性炎症，但代谢综合征的发病机制的背景下， 老龄化和艾滋病毒疾病仍然是该领域不完全理解的知识差距。NLRP 3（NOD- 3）炎性小体是一种细胞内蛋白复合物，它是细胞外基质的一部分， 先天性免疫应答，并介导caspase-1依赖性的pro-IL-1b和pro-IL-18裂解， 激活的形式。虽然NLRP 3炎性小体被PAMP激活，但越来越多的证据表明， NLRP3作为宿主代谢的传感器通过DAMP的作用，如通过广泛的细胞因子激活NLRP3所示。 代谢物。此外，NLRP3炎性小体激活依赖于线粒体功能。的nlrp3 炎性小体与胰岛素抵抗和其他代谢综合征的发展有关， 小鼠模型，并已在老年人和HIV感染的成年人中进行了最低限度的探索。的目的 本研究旨在确定年龄和HIV感染对NLRP 3炎性小体的影响， 与线粒体功能的关系通过比较以下受试者组，年轻人（21 - 35岁）， 以及有和无HIV感染的老年人（≥ 60岁）。目标1旨在描述NLRP 3 炎性小体及其与线粒体功能的关系，在外周血和骨髓细胞 脂肪组织目的2旨在表征通过激活代谢途径诱导的代谢途径， 通过RNA测序和CyTOF在来自外周血的髓样细胞中检测NLRP3炎性小体， 脂肪组织将结合临床特征收集两个目标的数据，包括 代谢综合征的组成部分。我们的假设是，年龄增长和艾滋病毒感染将导致 基线时NLRP3炎性小体功能失调，并伴有与 线粒体功能障碍-最终导致老年人代谢综合征的发展， 感染艾滋病毒的成年人。候选人萨帕塔博士是耶鲁大学传染病学院的传染病医生。 他组建了一个跨学科的导师委员会，拥有免疫学，衰老， 和新陈代谢。这一培训提案与包括辅导在内的职业发展计划相结合 免疫代谢的教学培训，重点是学习测序分析 数据，从而提供允许PI申请R01奖的工具。