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)

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要当前的证据表明，撒哈拉以南非洲面临着双重疾病负担，艾滋病毒和心脏在碰撞过程中，毫代谢性疾病似乎。这是由于Cardiometa-的日益加剧的加剧可归因于艾滋病毒的疾病，这将进一步影响该地区已经陷入困境的公共卫生资源。关于HIV和Cardiometa- - 因此，撒哈拉以南非洲人口中的葡萄酒是一个主要的知识差距。几个因素，包括线粒体功能障碍在内，与HIV相关的心脏代谢性疾病的发病机理有关舒适。线粒体功能障碍已与HIV和心脏代谢疾病以及先前的研究有关已经证明了在生活中的几种心脏代谢相关病理中的线粒体参与与艾滋病毒（PLWH）。尽管HIV相关心脏代谢疾病的共同基本机制仍然存在线粒体功能障碍难以捉摸可能唯一将心脏代谢疾病的发病机理驱动到更大的与没有艾滋病毒相比的人的程度。撒哈拉以南非洲的PLWH尤其容易受到Mi的影响由于固有和外在危险因素的独特收敛，包括暴露于流行病原体和高水平的炎症。在这项研究中，假设抗逆转录病毒疗法（ART） - 在撒哈拉以南非洲具有心脏代谢性疾病的经验，将显示出更大的线粒体与没有心脏代谢疾病的PLWH相比，功能障碍和无HIV的对照。该假设将在一项探索性的，横断面的研究中进行测试，该研究包括南非和肯尼亚的同伙。在特定目标中 1，线粒体呼吸功能（通过最新的高分辨率呼吸法和荧光测定法测量技术）将在患有艾滋病毒和艾滋病毒的参与者中进行比较，并且将确定是否线刺 - Drial功能障碍在患有心脏代谢疾病的PLWH中更为明显。在特定的目标2中，mRNA表达在有或没有的参与者中，将比较与线粒体功能和动力学相关的基因的sion HIV，将确定基因表达在患有心脏代谢疾病的PLWH中是否有所不同。关于- 包括炎症，免疫学和内分泌在内的培养病理生理过程，将测量为在目标1和2中补充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PLWH中存在线粒体功能障碍，并具有Cardiomet- 来自南非和肯尼亚的腹部疾病。这些结果可能使该地区的公共卫生受益，包括筛选有线粒体功能障碍风险的PLWH，修订第一线艺术，其中包括有线粒体的药物软骨毒性，对PLWH中心脏代谢疾病的强调。南方的新研究网络非洲，肯尼亚和美国将被伪造，以强大的能力发展重点。