Mitochondrial Haplotype Influences LV Dysfunction in Heart Failure

线粒体单倍型影响心力衰竭中的左心室功能障碍

基本信息

批准号：
8826620
负责人：
VICTOR M DARLEY-USMAR
金额：
$ 36.08万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-10 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8826620
关键词：
Adult Affect Aortic Valve Insufficiency Back Bioenergetics Cardiac Myocytes Cell Nucleus Code Coupling DNA Sequence Data Disease susceptibility Electron Transport Event Failure Fistula Functional disorder Gene Expression Generations Genes Genome Haplotypes Heart Heart failure In Vitro Inbred C3H Mice Inflammatory Inflammatory Response Lead Left Ventricular Remodeling Matrix Metalloproteinases Measurement Mediating Mitochondria Mitochondrial DNA Mitochondrial Matrix Mitochondrial Proteins Mitochondrial Swelling Mitral Valve Insufficiency Modeling Molecular Mouse Strains Mus Myofibrils Nitrogen Nuclear Oxidants Oxidative Stress Oxygen Pathologic Patients Phenotype Play Production Proteins Protons Renin-Angiotensin System Role Signal Transduction Stress Stretching Structure Testing Variant Vasodilator Agents extracellular improved in vivo insight mouse model new technology novel research study response targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Studies of volume overload (VO) of mitral and aortic regurgitation (MR and AR) show no benefit on LV remodeling using vasodilator drugs or renin-angiotensin system blockade. In the current project, we present preliminary data demonstrating the existence of matrix metalloproteinases (MMPs) within mitochondria and their activation with VO. The mitochondrial (mt) DNA haplotype of C57BL/6J compared to that of C3h/HeN mice have higher proton coupling and ROS generation. Therefore we hypothesize that the C57 mtDNA haplotype produces greater cardiomyocyte oxidative stress and bioenergetic dysfunction, mitochondrial MMP activation, and disruption of myofibrillar and mitochondrial structure in VO. ROS can act as signaling mechanisms to the nucleus. We also hypothesize that mitochondrial haplotype directs nuclear molecular signals that also produce a greater molecular inflammatory response and predict adverse LV remodeling and function in VO. We will use the C57 mouse with its nuclear background combined with C3H mtDNA (C57n:C3Hmt) mitochondrial nuclear exchange (MNX) mouse, to test whether mice with C3H mtDNA can rescue C57 from pathologic consequences of VO and vice versa in C3Hn:C57mt mice in the following specific aims. 1) Characterize the impact of mtDNA haplotype on cellular bioenergetics and LV function in VO. 2) Demonstrate that mtDNA haplotype determines increased mitochondrial oxidant production in VO and causes mitochondrial MMP activation. 3) Demonstrate that mtDNA haplotype influences nuclear molecular inflammatory response in the LV of mice subjected to the VO of ACF. This proposal with utilize the aortocaval fistula mouse model of VO, which integrates novel technology of measurements of bioenergetics of intact cardiomyocytes and oxidative stress in a MNX mouse model in which the mitochondrial (mt) DNA of one mouse strain is incorporated into the nuclear (n) genome of another (e.g., C57n:C3Hmt or C3Hn:C57mt).

描述（由申请人提供）：二尖瓣和主动脉瓣反流（MR 和 AR）的容量超负荷（VO）研究显示，使用血管扩张药物或肾素-血管紧张素系统阻断对左室重塑没有益处。在当前的项目中，我们提供了初步数据，证明线粒体内基质金属蛋白酶 (MMP) 的存在及其通过 VO 的激活。与 C3h/HeN 小鼠相比，C57BL/6J 的线粒体 (mt) DNA 单倍型具有更高的质子耦合和 ROS 生成。因此，我们假设 C57 mtDNA 单倍型会产生更大的心肌细胞氧化应激和生物能功能障碍、线粒体 MMP 激活以及 VO 中肌原纤维和线粒体结构的破坏。 ROS 可以充当细胞核的信号传导机制。我们还假设线粒体单倍型指导核分子信号，这些信号也会产生更大的分子炎症反应并预测不良的 LV 重塑和 VO 功能。我们将使用具有核背景的 C57 小鼠与 C3H mtDNA (C57n:C3Hmt) 线粒体核交换 (MNX) 小鼠结合，测试具有 C3H mtDNA 的小鼠是否可以将 C57 从 VO 的病理后果中拯救出来，反之亦然。在以下具体目标中。 1) 表征 VO 中 mtDNA 单倍型对细胞生物能学和 LV 功能的影响。 2) 证明 mtDNA 单倍型决定 VO 中线粒体氧化剂产量的增加并导致线粒体 MMP 激活。 3) 证明 mtDNA 单倍型影响接受 ACF VO 的小鼠 LV 中的核分子炎症反应。该提案利用 VO 的主动脉腔静脉瘘小鼠模型，该模型集成了 MNX 小鼠模型中完整心肌细胞生物能学和氧化应激测量的新技术，其中一种小鼠品系的线粒体 (mt) DNA 被整合到细胞核 (n) 中。 ) 另一个基因组（例如，C57n:C3Hmt 或 C3Hn:C57mt）。