权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Diastolic Heart Failure in HIV-1 infection

HIV-1 感染引起的舒张性心力衰竭

基本信息

批准号：
10491524
负责人：
KESHORE R BIDASEE
金额：
$ 62.52万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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：
2022-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10491524
关键词：
Anti-Retroviral Agents Area Arteriosclerosis Attenuated Autopsy Biochemical Biological Assay Blood Vessels Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cells Chronic Clinical Coronary Data Development Diabetes Mellitus Diastolic heart failure Disease Endothelial Cells Endothelium Enzymes Extravasation Fibrosis Fumarates Functional disorder Gene Transfer Genus Hippocampus Glycolysis HIV HIV Infections HIV-1 Health Care Costs Heart Heart Diseases Heart failure Hemoglobin Homeostasis Hospitalization Hospitals Hypoxia Hypoxia Inducible Factor Impairment Individual Infection Inflammation Ischemia Kinetics Lactoylglutathione Lyase Link Lung MAP Kinase Gene Measures Mediator of activation protein Modeling Molecular Mus Muscle Cells Myocardial Infarction Myocarditis Nitric Oxide Outcome Oxidative Stress Oxygen Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Pharmacotherapy Plasma Production Publishing Pulmonary Hypertension Pyruvaldehyde Regimen Research Smooth Muscle Myocytes Sudden Death Tenofovir Therapeutic Time Tissues Triose-Phosphate Isomerase Up-Regulation Viral Viremia Virus Virus Replication Visit base chrysin cytotoxic early onset emtricitabine humanized mouse in vivo inhibitor innovation macrophage mouse model normal aging novel novel therapeutics p38 Mitogen Activated Protein Kinase photoacoustic imaging prevent seropositive sex systemic inflammatory response tool transcription factor

项目摘要

Abstract: Contemporary estimates suggest that more than 40% of people living with chronic HIV-1 infection (PLWH) have diastolic heart failure (dHF), a harbinger for adverse clinical outcomes including pulmonary abnormalities, frequent hospitalizations, and sudden death. To date, the molecular causes for dHF in PLWH remain poorly understood. This paucity of information and a lack of treatment options have prompted the OAR to list “Strategies to Prevent and Treat HIV-Associated Heart Diseases” as areas of high priority for HIV research. We hypothesize that that “elevation of the cytotoxic glycolysis metabolite, methylglyoxal (MG) is a primary cause for dHF development in PLWH.” This elevation in MG is arising from HIV-1 induce upregulation of glycolysis in infected immunocytes followed by ischemia-induced increase in glycolysis in vascular cells and cardiac myocytes. This multi-PI project brings together the expertise of Drs. Keshore R. Bidasee (M-PI, heart failure) and Santhi Gorantla (M-PI, humanized mice and HIV-1 infection) with assistance from Dr. Prasanta Dash (HIV-1 eradication and cardiovascular complications), to (1) Define pathobiological trajectories of dHF in relation to MG levels in HIV-1 infected Hu-mice with and with ARD treatment; (2) Characterize mechanisms by which MG increases in HIV-I infected immunocytes and in myocytes, macrophages and vascular cells under with and without ARD and hypoxia (3) Show that lowering MG will blunt dHF in HIV-infected Hu-mice with and without ARD. Accomplishments of these aims will not only define a novel link between glycolysis and early-onset dHF in the setting of HIV-1 infection, but the data could pave the way for the development of urgently needed therapeutics to mitigate this disease in PLWH.

摘要：当代估计表明，超过40%的慢性HIV-1感染者（PLWH）舒张性心力衰竭（dHF），包括肺部异常在内的不良临床结果的先兆，频繁住院和猝死。迄今为止，PLWH中dHF的分子原因仍然很差明白信息的缺乏和治疗方案的缺乏促使OAR列出了“策略预防和治疗艾滋病毒相关的心脏病”作为艾滋病毒研究的优先领域。我们假设细胞毒性糖酵解代谢物甲基乙二醛（MG）升高是dHF的主要原因在PLWH的发展”。MG的这种升高是由HIV-1诱导感染者糖酵解上调引起的。免疫细胞中的糖酵解增加，随后缺血诱导的血管细胞和心肌细胞中的糖酵解增加。这多PI项目汇集了Keshore R. Bidasee（M-PI，心力衰竭）和Santhi Gorantla (M-PI，人源化小鼠和HIV-1感染）与Prasanta Dash博士的协助（HIV-1根除和心血管并发症），以（1）定义与HIV-1中MG水平相关的dHF病理生物学轨迹感染的Hu-小鼠和ARD治疗;（2）表征HIV-I中MG增加的机制感染的免疫细胞和在有和没有ARD下的肌细胞、巨噬细胞和血管细胞中，缺氧（3）表明降低MG将减弱有和无ARD的HIV感染的Hu小鼠中的dHF。这些目标的实现不仅将定义糖酵解和早发性dHF之间的新联系， HIV-1感染的背景，但这些数据可以为开发迫切需要的治疗方法铺平道路来减轻艾滋病病毒携带者的病情。