Altered mitochondrial function and HIV-associatedcardiometabolic disease in populations from South Africa and Kenya (MITO-SAKen)

南非和肯尼亚人群线粒体功能改变和 HIV 相关心脏代谢疾病 (MITO-SAKen)

• 批准号: 10704100
• 负责人: Hans Strijdom
• 金额: $ 15.42万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704100
• 关键词: Address; Adenosine Triphosphate; Africa South of the Sahara; African; Aging; Air Pollution; Apoptosis; Biogenesis; Cardiometabolic Disease; Cardiovascular system; Cell Aging; Cell Extracts; Chronic; Clinical Research; Coenzyme Q10; Communicable Diseases; Complement; Cross-Sectional Studies; Data; Development; Diabetes Mellitus; Disease; Eastern Africa; Elderly; Electron Transport; Endocrine; Epidemiology; Exposure to; Fluorometry; Fumarates; Funding; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Grant; HIV; HIV Infections; HIV/AIDS; Health Resources; High Density Lipoprotein Cholesterol; High Prevalence; Hyperglycemia; Hypertension; Hypertriglyceridemia; Immunologics; Impairment; In Vitro; Inflammation; Inflammatory; Institution; Integrase Inhibitors; Kenya; Kidney Diseases; Knowledge; Link; Liver diseases; Measures; Membrane Potentials; Metabolic; Metabolic syndrome; Mission; Mitochondria; Mitochondrial DNA; NIH Office of AIDS Research; National Institute of Diabetes and Digestive and Kidney Diseases; Nucleosides; Obesity; Oxidative Phosphorylation; Oxidative Stress; Participant; Pathogenesis; Pathology; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Polymerase Chain Reaction; Population; Populations at Risk; Predisposition; Process; Production; Public Health; RNA; Reactive Oxygen Species; Regimen; Research; Research Priority; Resolution; Respiration; Respiratory physiology; Reverse Transcriptase Inhibitors; Reverse Transcription; Risk; Risk Factors; Sampling; Smoking; South Africa; Southern Africa; Spirometry; Subgroup; Technology; Tenofovir; Testing; Time; Toxic effect; Transmembrane Transport; Tuberculosis; United States National Institutes of Health; Weight Gain; aged; antiretroviral therapy; burden of illness; cardiometabolic risk; cardiometabolism; co-infection; cohort; comorbidity; disorder risk; epidemiologic data; epidemiology study; experience; experimental study; forging; immune activation; infection rate; insight; lifestyle factors; low and middle-income countries; mRNA Expression; mitochondrial dysfunction; mitochondrial membrane; mortality; novel; pathogen; recruit; screening; trend

PROJECT SUMMARY Current evidence suggests that sub-Saharan Africa is facing a double burden of disease, with HIV and cardi- ometabolic disease seemingly on a collision course. This is compounded by the growing burden of cardiometa- bolic disease attributable to HIV, which will further impact already struggling public health resources in the region. The relative lack of epidemiological and mechanistic studies on the intersection between HIV and cardiometa- bolic disease in sub-Saharan African populations therefore represents a major knowledge gap. Several factors, including mitochondrial dysfunction, are implicated in the pathogenesis of HIV-associated cardiometabolic dis- ease. Mitochondrial dysfunction has been linked to both HIV and cardiometabolic disease and previous studies have demonstrated mitochondrial involvement in several cardiometabolic-related pathologies in people living with HIV (PLWH). Whilst a common underlying mechanism of HIV-associated cardiometabolic disease remains elusive, mitochondrial dysfunction may uniquely drive the pathogenesis of cardiometabolic disease to a greater extent in people with compared to without HIV. PLWH in sub-Saharan Africa are particularly susceptible to mi- tochondrial dysfunction due to a unique convergence of intrinsic and extrinsic risk factors, including exposure to endemic pathogens and high levels of inflammation. In this study, it is hypothesized that antiretroviral therapy (ART)-experienced PLWH with cardiometabolic disease in sub-Saharan Africa will show greater mitochondrial dysfunction compared to PLWH without cardiometabolic disease and controls without HIV. The hypothesis will be tested in an exploratory, cross-sectional study comprising cohorts in South Africa and Kenya. In Specific Aim 1, mitochondrial respiratory function (measured by state-of-the-art high resolution respirometry and fluorometry technology) will be compared in participants with and without HIV, and it will be determined whether mitochon- drial dysfunction is more pronounced in PLWH with cardiometabolic disease. In Specific Aim 2, mRNA expres- sion of genes linked to mitochondrial function and dynamics will be compared in participants with and without HIV, and it will be determined whether gene expression is different in PLWH with cardiometabolic disease. Re- lated pathophysiological processes, including inflammatory, immunological and endocrine, will be measured to complement the mitochondrial function and gene expression experiments in Aims 1 and 2. This exploratory study will provide preliminary evidence that heightened mitochondrial dysfunction is present in PLWH with cardiomet- abolic disease from South Africa and Kenya. These results may benefit public health in the region, including screening of PLWH at risk of mitochondrial dysfunction, revision of 1st line ART that includes drugs with mito- chondrial toxicity, and stronger emphasis on cardiometabolic disease in PLWH. New research networks in South Africa, Kenya and the US will be forged, with a strong capacity development focus.

项目概要 目前的证据表明，撒哈拉以南非洲地区面临着艾滋病毒和心脏病的双重疾病负担。 代谢疾病似乎正在发生冲突。日益增加的心脏代谢负担使情况变得更加复杂。 艾滋病毒引起的代谢性疾病，这将进一步影响该地区本已陷入困境的公共卫生资源。 关于 HIV 与心脏代谢之间的交叉点的流行病学和机制研究相对缺乏 因此，撒哈拉以南非洲人口的代谢性疾病是一个重大的知识差距。几个因素， 包括线粒体功能障碍，与 HIV 相关心脏代谢紊乱的发病机制有关。 舒适。线粒体功能障碍与艾滋病毒和心脏代谢疾病以及之前的研究有关 已证明线粒体参与了人们的几种心脏代谢相关病理 艾滋病毒感染者（PLWH）。虽然 HIV 相关心脏代谢疾病的共同潜在机制仍然存在 难以捉摸的线粒体功能障碍可能独特地将心脏代谢疾病的发病机制推向更大的范围 与未感染艾滋病毒的人相比，其程度。撒哈拉以南非洲地区的 PLWH 特别容易受到病毒感染 由于内在和外在危险因素（包括暴露于环境）的独特融合而导致软骨功能障碍 地方性病原体和高水平的炎症。在这项研究中，假设抗逆转录病毒治疗 撒哈拉以南非洲地区患有心脏代谢疾病的（ART）经验丰富的艾滋病病毒感染者将表现出更大的线粒体 与没有心脏代谢疾病的感染者和没有艾滋病毒的对照相比，功能障碍。该假设将 在一项由南非和肯尼亚的队列组成的探索性横断面研究中进行测试。特定目标 1、线粒体呼吸功能（通过最先进的高分辨率呼​​吸测定法和荧光测定法测量 技术）将在有和没有艾滋病毒的参与者中进行比较，并将确定线粒体是否 患有心脏代谢疾病的感染者的干燥功能障碍更为明显。在特定目标 2 中，mRNA 表达- 将在有和没有的参与者中比较与线粒体功能和动力学相关的基因。 HIV，并且将确定患有心脏代谢疾病的 PLWH 的基因表达是否不同。关于- 将测量相关的病理生理过程，包括炎症、免疫和内分泌， 补充目标 1 和 2 中的线粒体功能和基因表达实验。这项探索性研究 将提供初步证据表明患有心脏病的 PLWH 中线粒体功能障碍加剧 来自南非和肯尼亚的代谢性疾病。这些结果可能有益于该地区的公共卫生，包括 筛查有线粒体功能障碍风险的感染者，修订第一线抗逆转录病毒疗法，其中包括具有线粒体功能的药物 软骨毒性，并更加重视 PLWH 的心脏代谢疾病。南方的新研究网络 非洲、肯尼亚和美国将得到加强，重点是能力建设。