Cardiomyocyte Proliferation & Ventricular Morphogenesis

描述（由申请人提供）：促进心肌细胞 在胎儿期不能诱导增殖， 产后生活，只是知之甚少。我的实验室研究了心脏 缺乏视黄酸受体RXRa的小鼠胚胎发育，其中 心室腔中致密区的形成未能启动，导致 在发育不良的腔室中，这与胎儿的活力不相容。我们有 先前描述了这种表型，并表明， 在心室发育过程中视黄酸不出现在心肌中， 而是发生在一个不同的细胞谱系中， 心肌增殖和随后的心室腔形态发生。 模型：基于本申请中提供的新数据，我提出维甲酸 酸信号最初由心外膜中的RXR α转导，从而 诱导一种或多种分泌的营养生长因子的表达， 对心肌层的影响在较老的胚胎和出生后的动物中， 对这些因素的刺激不敏感。为了解决这个问题，我建议 以下具体目标： 具体目标1：明确RXR α在心外膜中的作用。组织特异 小鼠胚胎中的灭活和转基因操作以及病毒感染 在鸡胚中，提出证明RXR α功能发生在 心外膜 具体目的2：鉴定心外膜细胞分泌的因子， 对心肌有营养作用的视黄酸的反应。生化 纯化加基于基因的发现方法被提出来鉴定 心外膜细胞分泌的维甲酸和RXRa依赖性因子 方式 具体目标3：确定心肌反应的关键成分， 心外膜细胞分泌的营养因子。我建议识别信号 胎儿心肌细胞中的转导元件介导对 营养刺激以及导致缺乏反应的变化 在出生后的心肌中。

DESCRIPTION (provided by applicant): The mechanisms which promote cardiomyocyte proliferation during fetal life, and which fail to induce proliferation during postnatal life, are only poorly understood. My lab has studied cardiac development in mouse embryos lacking the retinoic acid receptor RXRa, in which compact zone formation in the ventricular chamber fails to initiate, resulting in a hypoplastic chamber that is incompatible with fetal viability. We have previously described this phenotype and shown that the initial response to retinoic acid during ventricular development does not occur in the myocardium, but rather occurs in a distinct cell lineage which then secondarily supports myocardial proliferation and subsequent ventricular chamber morphogenesis. Model: Based on new data presented in this application, I propose that retinoic acid signaling is initially transduced by RXRa in the epicardium, thereby inducing expression of one or more secreted growth factors which are trophic for the myocardium. Myocardium in older embryos and in postnatal animals is refractory to stimulation by these factors. To address this model, I propose the following Specific Aims: Specific Aim 1: To define the role of RXRa in the epicardium. Tissue-specific inactivation and transgenic manipulation in mouse embryos, and viral infection in chick embryos, are proposed to demonstrate that RXRa function occurs in the epicardium. Specific Aim 2: To identify the factor(s) secreted by epicardial cells in response to retinoic acid that are trophic for the myocardium. Biochemical purification plus gene-based discovery approaches are proposed to identify the factors secreted by epicardial cells in a retinoic acid- and RXRa-dependent manner. Specific Aim 3: To define the critical components of the myocardial response to epicardial cell secreted trophic factor(s). I propose to identify the signal transduction elements in fetal cardiocytes which mediate the response to trophic stimulation, as well as changes which account for the lack of response in postnatal myocardium.