Restoration of Myocardial Healing Through Cardiokine Secretion

由心脏分泌的蛋白质称为心脏因子。分泌后，心脏因子，如细胞因子，生长 启动子和干细胞归巢因子影响缺血性损伤以及干细胞存活， 移植但是缺血损伤蛋白质折叠和分泌，并对干细胞介导的 再生然而，我们发现了一个分泌过程，抵抗这种抑制，使释放 某些有益的心血管因子，就在最需要的时候。本研究的目的是 检查心肌细胞中分泌过程的功能和分子机制， 在体外和体内以及心脏干细胞中。我们在研究有益的 心脏因子，中脑星形胶质细胞源性神经营养因子（MANF），它存在于 内质网/肌浆网（ER/SR）。我们的假设是：1）GRP 78调节 有益的ER通过介导心肌细胞和心脏祖细胞的 蛋白质在ER/SR中的条件性保留，和2）CPC特别地配置有新的胞质溶质， GRP 78的一种形式，在内质网应激期间增强存活以及心血管因子分泌。 通过使用MANF作为模型心脏因子、GRP 78功能获得和丧失、培养的细胞和 小鼠心脏，1AV 9介导的体内基因转移，以及以下零距离活细胞交联 具体目的：1-确定GRP 78调节心肌细胞分泌心因子的机制， 心肌细胞，2-评估GRP 78调节的心脏中的心脏因子分泌，在体内，并确定影响 干扰这种分泌对缺血性损伤和再生的影响，以及3-检查GRP 78在缺血性损伤中的作用。 ER以及一种新的胞质形式的GRP 78对心因子分泌、对ER应激的反应 心脏干细胞的存活。这些研究的结果将有助于治疗策略的设计 旨在增强有益的心血管因子的分泌， 再生

Proteins secreted by the heart are called cardiokines. After secretion, cardiokines, such as cytokines, growth promoters and stem cell homing factors affect ischemic damage, as well as stem cell survival and engraftment. But ischemia impairs protein folding and secretion, and negatively impacts stem cell-mediated regeneration. However, we discovered a secretion process that resists this inhibition, enabling the release of certain beneficial cardiokines, just when they are needed the most. The objectives of this study are to examine the functions of, and molecular mechanisms governing this secretion process in cardiac myocytes, in vitro and in vivo, and in cardiac stem cells. We discovered this process while studying the beneficial cardiokine, mesencephalic astrocyte-derived neurotrophic factor (MANF), which resides in the endoplasmic/sarcomplasmic reticulum (ER/SR). Our hypothesis is that 1) GRP78 regulates the secretion of beneficial ER stress cardiokines from cardiac myocytes and cardiac progenitor cells by mediating the conditional retention of proteins in the ER/SR, and 2) CPCs are specially configured with a novel cytosolic form of GRP78 that enhances survival, as well as cardiokine secretion during ER stress.We will address this hypothesis by using MANF as a model cardiokine, GRP78 gain- and loss-of-function, cultured cells and mouse hearts, /\AV9-mediated in vivo gene transfer, and zero-distance live cell cross linking in the following specific aims: 1- to determine the mechanism by which GRP78 regulates cardiokine secretion from cardiac myocytes, 2- to assess GRP78-regulated cardiokine secretion in the heart, in vivo, and determine the effects of disrupting this secretion on ischemic damage and regeneration, and 3- to examine the effects of GRP78 in the ER, as well as a novel, cytosolic form of GRP78 on cardiokine secretion, responses to ER stress and survival of cardiac stem cells. The results of these studies will facilitate the design of therapeutic strategies aimed at enhancing the secretion of beneficial cardiokines that minimize damage and maximize regeneration.