Elucidation of molecular networks required to limit cardiac cell number

在发育过程中，各种信号相互协调，使器官达到适当的大小， 才能正常运作。在脊椎动物的心脏发育中，已知有几种途径可以促进 诱导和心脏的生长，而很少有途径是已知的限制心脏的大小。我 长期目标是了解器官如何快速达到其大小。这笔赠款的具体目的是 阐明限制心脏大小所需的分子途径和细胞机制 在斑马鱼的发育过程中。在奖励的指导阶段，我描述了一种机制， 由此hoxbSb，RA信号传导的下游效应物，非自主地限制心房细胞数量， 邻近的前肢区域这些研究有助于为器官发生提供新的见解， 潜在的机制，可能是影响心脏和心脏的发育综合征的基础。 前肢尽管我进行了初步的研究，我们仍然不了解心肌细胞增加的本质， RA信号缺陷的胚胎。在具体目标1中，1将进行克隆分析实验，以确定 哪些细胞的命运会直接受到心肌细胞数量增加的影响。此外，我们不明白 hoxbSb的下游效应器如何限制心房细胞数量。在具体目标2中，1将使用 用于表征hoxbSb下游候选效应基因的功能丧失方法， 需要专门限制心房细胞的形成。从我们对RA下游效应物的初步筛选中， 信号，我们还不知道任何基因，具体限制心室细胞的数量。具体目标 3，1将使用功能丧失的方法来确定RA信号传导的下游效应物， 限制心室细胞数量可能除了RA信号外，其他信号通路也参与了 限制了心肌细胞的形成。在具体目标4中，1将描述可以修饰 RA信号对心脏大小的影响。考虑到RA信号作用的许多背景，包括心脏 再生，肺分支，干细胞分化和癌症生物学，我的发现很可能会 还对人类健康和治疗学的最终发展具有广泛的应用。

During development, a variety of signals are coordinated that allow an organ to attain its proper size, which Is required for its normal function. In vertebrate heart development, several pathways are known to promote induction and growth of the heart, while few pathways are known to restrict the size of the heart. My long-term goal Is to understand how organs pnsperly achieve their size. The specific aims of this grant are to elucidate the molecular pathways and cellular mechanisms that are required to restrict the size of the heart during development using zebrafish. During the mentored phase of the award, I characterized a mechanism whereby hoxbSb, a downstream effector of RA signaling, non-autonomously restricts atrial cell number from the adjacent forelimb field. These studies helped to provide novel insights into organogenesis and potentially mechanisms which niay underly developmental syndromes affecting both the heart and the forelimb. Despite my initial studies, we still do not understand the nature of the increase in cardiac cells in RA signaling deficient embryos. In Specific Aim 1,1 will perform clonal analysis experiments to determine what cell fates may be directly affected by the increase In cardiac cells. Furthermore, we do not understand how downstream effectors of hoxbSb may be acting to restrict atrial cell number. In Specific Aim 2,1 will use loss of function approaches to characterize candidate effector genes downstream of hoxbSb that are required to specifically restrict atrial cell fonnatlon. From our initial screen of downstream effectors of RA signaling, we do not yet know of any genes that specifically restrict ventricular cell number. In Specific Aim 3,1 will use loss of function approaches to identify downstream effectors of RA signaling specifically required to limit ventricular cell number. It is likely other signaling pathways besides RA signaling are involved in restricting cardiac cell formation. In Specific Aim 4,1 will characterize novel mutants that can modify the Impact of RA signaling on heart size. Given the many contexts in which RA signaling acts, Including cardiac regeneration, lung branching, stem cell differentiation, and cancer biology, it is likely that my findings will also have a broad range of applications toward human health and the eventual development of therapeutics.