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

Sex-specific modulators of mitochondrial function

线粒体功能的性别特异性调节剂

基本信息

批准号：
79521647
负责人：
Professorin Dr. Vera Regitz-Zagrosek
金额：
--
依托单位：
Max-Delbrück-Centrum für Molekulare Medizin (MDC) in der Helmholtz-Gemeinschaft
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/79521647?language=en
关键词：
Sex specific modulators mitochondrial function

项目摘要

Female mice develop more physiological myocardial hypertrophy than males in response to exercise. Our project investigates the mechanisms leading to these sex differences. We have identified target mitochondrial genes/proteins (PGC-1a, MEF2A, NRF1/2, TFAM) and pathways (PI3K/AKT and p38-MAPK) that are activated only in the hearts of female running mice or in in-vitro studies with cardiomyocytes in the presence of estrogen (E2). The preliminary results suggest that female sex and/or E2/estrogen receptors (ER) strongly influence mitochondrial biogenesis and function. To test this hypothesis, we will analyze the sex-specific regulation of nuclear and mitochondrial key enzymes involved in mitochondrial biogenesis and respiratory function (oxygen consumption, and ATP-content) in a mouse model of exercise-induced myocardial hypertrophy. To analyze the molecular mechanisms by which E2-activated ER regulates mitochondrial biogenesis and function, we will determine the activation of PI3K/AKT and p38-MAPK pathways, and its downstream molecule, peroxisome proliferator-activated receptor-y (PPAR-y) coactivator 1a (PGC-1a), in cultured cells. We will test the transcriptional regulation of myocyte enhancer factor-2 (MEF2A), nuclear respiratory factor (NRF1/2), and mitochondrial transcription factor A (TFAM) that are regulated by PGC-1a. We will investigate the import of nuclear-encoded gene products into the mitochondria. Finally, we will clarify the specific role of ERa and ERß on metabolic changes during the development of myocardial hypertrophy in mouse models with heartspecific deletion of ERa and ERß, respectively. This study will give significant new insight into the protective mechanism of female sex and/or E2/ER on mitochondrial biogenesis and function in HF.

雌性小鼠比雄性小鼠对运动的反应更大。我们的项目调查导致这些性别差异的机制。我们已经确定了目标线粒体基因/蛋白质（PGC-1a，MEF 2A，NRF 1/2，TFAM）和途径（PI 3 K/AKT和p38-MAPK），它们仅在雌性跑步小鼠的心脏或在雌激素（E2）存在下的心肌细胞体外研究中被激活。初步结果表明，女性性别和/或E2/雌激素受体（ER）强烈影响线粒体的生物发生和功能。为了验证这一假设，我们将分析在运动诱导的心肌肥大的小鼠模型中参与线粒体生物合成和呼吸功能（氧消耗和ATP含量）的核和线粒体关键酶的性别特异性调节。为了分析E2激活的ER调节线粒体生物发生和功能的分子机制，我们将在培养的细胞中确定PI 3 K/AKT和p38-MAPK通路及其下游分子过氧化物酶体增殖物激活受体-γ（PPAR-y）共激活因子1a（PGC-1a）的激活。我们将测试由PGC-1a调节的肌细胞增强因子-2（MEF 2A）、核呼吸因子（NRF 1/2）和线粒体转录因子A（TFAM）的转录调节。我们将研究核编码的基因产物进入线粒体。最后，我们将阐明ER α和ER β在心脏特异性缺失ER α和ER β的小鼠模型心肌肥大发展过程中对代谢变化的具体作用。本研究将为深入了解女性性别和/或E2/ER对HF线粒体生物发生和功能的保护机制提供重要的新见解。