Involvement of BAG3 in HIV-1 induced cardiomyopathy

BAG3 参与 HIV-1 诱导的心肌病

基本信息

批准号：
9282635
负责人：
Joseph Y Cheung
金额：
$ 72.79万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9282635
关键词：
Acquired Immunodeficiency Syndrome Address Adult Affect Age Aging Animal Model Animals Antibodies Apoptosis Attention Autophagocytosis Autophagosome BAG3 gene Biology Blood Circulation Calcium Signaling Cardiac Cardiac Myocytes Cardiac development Cardiomyopathies Cardiovascular system Cell Culture Techniques Cells Cessation of life Clinical Clinical Research Comorbidity Complex Development Dilated Cardiomyopathy Disease Ensure Equilibrium Etiology Event Excision Exhibits F-Actin Family Filament Functional disorder Gender Gene Expression Genes Genetic Transcription HIV HIV-1 Heart Heart Diseases Heart Transplantation Heart failure Heritability Homeostasis Human Impairment Incidence Individual Infection Injury Knockout Mice Laboratories Laboratory Animal Models Laboratory Animals Lead Left Ventricular Dysfunction Link Longevity Maintenance Mechanical Stress Mechanics Mediating Meta-Analysis Modeling Molecular Mus Muscle Cells Mutation Myocardial dysfunction Myocardium Myofibrils Organ Outcome Study Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Physiological Plasma Play Population Population Control Predisposition Production Prognostic Marker Proteins Quality Control Reporting Research Research Personnel Risk Risk Factors Role Sampling Secondary to Severities Severity of illness Signs and Symptoms Stimulus Stress-Induced Protein Structure Survival Rate System Testing Therapeutic Time Tissues Transgenic Mice Ubiquitination Ventricular Viral reservoir Virus Latency actin capping protein antiretroviral therapy cardiogenesis clinical development filamin genetic regulatory protein heart function improved in vivo mouse model myopodin prevent protein degradation public health relevance response sensor targeted treatment tat Protein uptake

项目摘要

DESCRIPTION: While long term combined antiretroviral therapy (cART) has greatly improved survival rates among AIDS patients, a substantial proportion of HIV-1 infected individuals continue to develop comorbidities including heart failure (HF) secondary to left ventricular dysfunction at higher rates than non-HIV-1 individuals. The underlying mechanisms whereby HIV-1 increases susceptibility to HF remain poorly understood. In this respect, HIV-1 Tat, which is produced and released by the latent viral reservoir and upon its circulation can be taken up by uninfected cells, has received special attention due to its ability to induce an array of dysregulatory events that perturb cell and organ function. HIV-1 Tat has the capacity to induce injury and promote death in a broad range of cells including myocytes, and its expression promotes cardiac disease in laboratory animals. Our recent studies demonstrate that HIV-1 Tat physically associates with BAG3, a stress induced protein which is involved in protein quality control, and modulates autophagy and apoptosis. BAG3 is critical for normal cardiac development and maintenance as BAG3 knockout mice develop left ventricular (LV) dysfunction and have a shortened lifespan. Furthermore, recent studies have identified a potential role for BAG3 in patients with HF as heterozygous mutations that decrease the level of BAG3 have been identified in patients with HF within families who develop a heritable form of dilated cardiomyopathy. Moreover, ventricular myocardium isolated from failing human hearts examined at the time of heart transplantation exhibit nearly 50% reduction in BAG3 levels in cardiac tissue, all of which supports the importance of BAG3 for healthy heart function. At the subcellular level, the association of BAG3 with the actin capping protein, CapZ?1, promotes its complexation with Hsp70, events that stabilize CapZ?1and facilitate its proper subcellular distribution in cardiomyocytes. In addition, BAG3 is an important regulator of filamin and myopodin and regulates protein turnover by autophagy in cardiomyocytes. Our preliminary results suggest that the interplay between BAG3 and HIV-1 Tat impacts the ability of BAG3 to regulate several pathways involved in the structural and functional integrity of cardiomyocytes. Thus, one can envision a model in which the inactivation of BAG3, upon its association with HIV-1 Tat, recapitulates the clinical manifestations seen in patients with heart failure associated with low/dysfunctional BAG3. By capitalizing on the expertise of two groups of accomplished investigators in cardiovascular research and in HIV-1 pathogenesis and BAG3 biology, we will investigate the cellular and molecular mechanisms involved in HIV-1 induced cardiomyopathy in cell cultures, animal models, and clinical samples. The outcome of these studies will provide a unique set of information aimed at developing prognostic biomarkers of disease severity and therapeutic strategies for treating HIV-1 associated cardiomyopathy.

描述：虽然长期组合的抗逆转录病毒疗法（CART）在AIDS患者中的存活率大大提高，但很大一部分HIV-1感染的个体继续发展合并症，包括以高于非HIV-1个体的速率高于左心室功能障碍的心力衰竭（HF）。 HIV-1提高对HF的敏感性的基本机制仍然对理解不足。在这方面，由潜在病毒储层产生和释放的HIV-1 TAT及其循环后可以被未感染的细胞吸收，由于其能够诱导扰乱细胞和器官功能的一系列失调事件的能力，因此受到了特别的关注。 HIV-1 TAT具有在包括肌细胞在内的广泛细胞中诱导损伤和促进死亡的能力，其表达促进了实验动物的心脏病。我们最近的研究表明，HIV-1 TAT与BAG3物理缔合，BAG3是一种应激诱导的蛋白质，参与蛋白质质量控制，并调节自噬和凋亡。 BAG3对于正常的心脏发育和维护至关重要，因为BAG3基因敲除小鼠发育左心室（LV）功能障碍，并且寿命缩短。此外，最近的研究已经确定了BAG3在HF患者中的潜在作用是杂合突变，这些突变降低了BAG3水平的HF患者在HF患者的家庭中，这些患者在发展出一种可遗传的遗传性心肌病形式的家庭中。此外，在心脏移植时检查的人心脏中分离出的室心肌均显示出心脏组织中BAG3水平的降低近50％，所有这些都支持BAG3对健康心脏功能的重要性。在亚细胞水平上，BAG3与肌动蛋白限值蛋白Capz？1的关联促进了其与HSP70的络合，稳定Capz？1的事件并促进了其在心肌细胞中的适当亚细胞分布。此外，BAG3是丝霉素和肌无毒素的重要调节剂，可以通过心肌细胞自噬来调节蛋白质更新。我们的初步结果表明，BAG3和HIV-1 TAT之间的相互作用会影响BAG3调节心肌细胞结构和功能完整性涉及的几种途径的能力。因此，可以设想一个模型，其中BAG3与HIV-1 TAT的关联后，可以概括与心力衰竭相关的患者中看到的临床表现。带有低/功能障碍的Bag3。通过利用两组在心血管研究以及HIV-1发病机理和BAG3生物学领域的成熟研究者的专业知识，我们将研究HIV-1参与HIV-1诱导的细胞和分子机制在细胞培养物，动物模型和临床样品中诱导的心肌病。这些研究的结果将提供一组独特的信息，旨在开发疾病严重程度和治疗HIV-1相关心肌病的治疗策略的预后生物标志物。