VIRAL-HOST INTERACTIONS IN SIV CARDIAC DYSFUNCTION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。HIV相关性心肌病是一种常见且严重的HIV并发症，但其潜在的病理生理学机制却知之甚少。这一建议的中心假设是，SIV感染猕猴发生的功能性心脏损伤是由于SIV感染导致心脏中与巨噬细胞激活相关的选择性基质金属蛋白酶(MMPs)合成和激活增加所致。目的1：通过对SIV感染猕猴心功能的综合分析，探讨SIV感染猕猴心功能障碍的演变过程，明确心功能障碍与心肌巨噬细胞激活等炎症反应之间的关系。目的二：确定嗜巨噬细胞的SIV毒株在心脏内的复制是否是心功能障碍发生的先决条件。目的三：探讨SIV感染心脏巨噬细胞是否刺激基质金属蛋白酶的激活，从而导致心功能不全。这些研究将为在感染SIV的猕猴中进行干预性研究奠定基础，这些研究将针对特定的MMPs来预防心脏功能障碍

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HIV-associated cardiomyopathy is a frequent and serious HIV complication, yet the underlying pathophysiology is poorly understood. The central hypothesis of this proposal is that functional cardiac impairment that develops in SIV-infected macaques results from both increased synthesis and activation of selective matrix metalloproteinases (MMPs) associated with macrophage activation driven by SIV infection in the heart. There are 3 specific aims: Aim One: To determine the evolution of cardiac dysfunction in SIV-infected macaques based on comprehensive serial echoDoppler and pressure-volume relation analysis and to define the relationship between cardiac dysfunction and inflammatory responses in the heart including myocardial macrophage activation. Aim Two: To determine whether replication of macrophage-tropic SIV strains in the heart is a prerequisite for the development of cardiac dysfunction. Aim Three: To determine whether activation of matrix metalloproteinases are stimulated by SIV-infection of macrophages in the heart and lead to cardiac dysfunction. These studies will set the stage for performing interventive studies in SIV-infected macaques using approaches to target specific MMPs to prevent cardiac dysfuncti