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: 10433974
• 负责人: Heidi J Zapata
• 金额: $ 22.66万
• 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/10433974
• 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; 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： 老龄化和老龄化艾滋病毒感染者的特点是代谢率增加 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、与年龄相关的促炎症环境有关—— 称为“炎症衰老”——其特征是细胞因子、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 （PAMP）和损伤相关分子模式（DAMP）被认为有助于年龄相关 慢性炎症，但代谢综合征发病机制的潜在机制 老龄化和艾滋病毒疾病的研究仍然是该领域不完全了解的知识空白。 NLRP3（NOD- 类似于含有吡啶结构域的受体 3) 炎性体是一种细胞内蛋白质复合物，是 先天免疫反应并介导 pro-IL-1b 和 pro-IL-18 的 caspase-1 依赖性裂解 激活的形式。虽然 NLRP3 炎症小体是由 PAMP 激活的，但越来越多的证据表明 NLRP3 通过 DAMP 作为宿主代谢传感器的作用，如 NLRP3 被广泛的激活所示 代谢物。此外，NLRP3 炎症小体的激活依赖于线粒体功能。 NLRP3 炎症小体与胰岛素抵抗和其他代谢综合征的发生有关 小鼠模型，并且在老年人和艾滋病毒感染者中进行了很少的探索。目的 该提案旨在确定年龄和 HIV 感染对 NLRP3 炎性体及其作用的影响 通过比较以下几组受试者，年轻人（21-35）， 以及感染或未感染 HIV 的老年人（≥ 60 岁）。目标 1 旨在描述 NLRP3 的特征 外周血和骨髓细胞中的炎症小体及其与线粒体功能的关系 脂肪组织。目标 2 旨在描述由激活的代谢途径所诱导的代谢途径。 通过 RNA 测序和 CyTOF 检测外周血和骨髓细胞中的 NLRP3 炎性体 脂肪组织。来自这两个目标的数据将结合临床特征进行收集，包括 代谢综合征的组成部分。我们的假设是，年龄的增长和艾滋病毒感染将导致 NLRP3 炎症小体功能在基线时失调，并且激活与 线粒体功能障碍——最终导致老年人和老年人代谢综合征的发生 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一名传染病医生 医学，他组建了一个跨学科指导委员会，拥有免疫学、衰老、 和新陈代谢。该培训建议附有职业发展计划，其中包括指导 和免疫代谢方面的教学培训，另外重点是学习测序分析 数据，从而提供 PI 申请 R01 奖项的工具。