Cellular, Genetic and Descriptive Analysis of Drosophila Heart Development

阐明调节心脏发育的分子途径对于我们理解心脏的形成至关重要。在人类中，先天性心脏缺陷是最常见的出生缺陷之一，在活产和死胎中的发生率分别为1%和10%。调控心脏发育的遗传和分子事件才刚刚开始在脊椎动物和无脊椎动物模型系统中进行探索。这项工作的初步见解表明，在发育中的心脏和它们的脊椎动物同源物中表达的果蝇基因在结构、表达和功能上具有显著的保守性。这些研究以及来自基因组项目的数据支持了这样的观点，即许多生物过程的基本结构在苍蝇和人类之间是保守的。因此，旨在了解控制果蝇心脏发育的遗传、细胞和分子机制的研究应该产生对心脏发育的基本见解。这项拨款的重点是剖析组成果蝇心脏的不同类型细胞的发育机制并确定其身份。目前的果蝇心脏发育模型在很大程度上依赖于对仅调节一小部分(~10%)心脏细胞发育的机制的分析。为了更全面地了解心脏发育，阐明促进所有心脏细胞发育的遗传、细胞和分子机制是至关重要的。这笔赠款的第一个具体目标是创建所有心脏细胞的基因表达、细胞分裂和细胞谱系图。这一目标的完成将在单细胞分辨率下建立正常心脏发育的描述性基础，我们和其他人可以从这个基础上启动对调节心脏发育的遗传机制的系统研究。第二个具体目标建议(I)剖析所有心脏细胞的模式和指定命运的遗传调控机制，以及(Ii)对调节心脏中形成的收缩细胞数量的两个基因进行详细的表型和分子表征。这些方法的结合应该会为协调果蝇心脏发育的遗传、细胞和分子机制描绘出一幅越来越清晰的图景。

0077727SkeathThe elucidation of the molecular pathways that regulate heart development is critical to our understanding of heart formation. In humans, congenital heart defects are one of the most frequent birth defects and occur at an incidence of 1% in live births and 10% in stillborns. The genetic and molecular events that regulate heart development are just beginning to be explored in vertebrate and invertebrate model systems. Initial insights from this work demonstrate a remarkable conservation of structure, expression and function between Drosophila genes expressed in the developing heart and their vertebrate homologs. These studies as well as data from genome projects support the idea that the fundamental architecture of many biological processes are conserved between flies and humans. Thus, research that aims to understand the genetic, cellular and molecular mechanisms that control Drosophila heart development should yield basic insights into heart development in general.The focus of this grant is to dissect the developmental mechanisms that pattern and specify the identity of the different types of cells that make up the Drosophila heart. Present models of Drosophila heart development rely heavily on the analysis of the mechanisms that regulate the development of only a small minority (~10%) of heart cells. To obtain a more comprehensive picture of heart development, it is critical to clarify the genetic, cellular and molecular mechanisms that promote the development of all heart cells. The first specific aim of this grant proposes to create a gene expression, cell division and cell lineage map of all heart cells. The completion of this aim will establish a descriptive foundation of normal heart development at the single cell resolution from which we and others can initiate systematic studies on the genetic mechanisms that regulate heart development. The second specific aim proposes (i) to dissect the genetic regulatory mechanisms that pattern and specify the fate of all heart cells, and (ii) to perform a detailed phenotypic and molecular characterization of two genes that regulate the number of contractile cells that form in the heart. The integration of these approaches should paint an increasingly lucid picture of the genetic, cellular and molecular mechanisms that orchestrate Drosophila heart development.