Structural characterization of protein complexes involved in embryogenesis.

描述（由申请人提供）：出生缺陷，如影响心血管（如主动脉缩窄）、神经系统（如脊柱裂）和颅面发育（如腭裂）的出生缺陷，在美国造成大约20%的婴儿死亡，并给医疗保健系统带来超过每年数十亿美元的负担。这些缺陷通常是胚胎发生中断的结果，胚胎发生依赖于关键通路的严格调控，包括Wnt、Hedgehog、Notch、PAR和骨形态发生肽/TGF β。然而，参与这些途径的许多蛋白质复合物缺乏详细的分子表征，更多的仍有待发现。针对胚胎组织的大规模蛋白质组学研究正开始系统地识别大量蛋白质。利用这些数据，我建议开发新的方法来结构和功能表征与胚胎发生相关的蛋白质复合物。具体来说，我将开发新的计算工具(I)对近端相互作用（即蛋白质亚复合物）进行数据分析以及（ii）计算蛋白质化学计量学。然后，我将整合这些信息来构建结构模型，既能表征个体复杂功能，又能识别它们在发育失败中的作用。这些结果将提供与胚胎发生相关的蛋白质复合物的机制理解，并有可能发现治疗发育失败的治疗靶点。此外，这里开发的方法将提供分析几乎任何生物系统的能力，因此应该对许多疾病的研究具有广泛的意义。

DESCRIPTION (provided by applicant): Birth defects, such as those effecting cardiovascular (e.g. Coarctation of the Aorta), nervous system (e.g. Spina bifida) and craniofacial development (e.g. Cleft Palate) are responsible for roughly 20% of infant deaths in the United States and place an exceeding burden on the health care system amounting to billions of dollars each year. Such defects are often the result of disruptions in embryogenesis, which depends on tight regulation of key pathways including Wnt, Hedgehog, Notch, PAR, and Bone morphogenetic peptide/TGF beta. Many of the protein complexes involved in these pathways however lack detailed molecular characterization, and more still remain to be discovered. Large-scale proteomics efforts focused on embryonic tissues are beginning to systematically identify proteins in vast numbers. Using these data, I propose to develop new methods to structurally and functionally characterize protein complexes associated with embryogenesis. Specifically, I will develop novel computational tools (i) to datamine for proximal interactions (i.e. protein subcomplexes) as well as (ii) to calculate protein stoichiometry. I will then integrate this information to build structural models capable of both characterizing individual complex functions as well as identifying their role in developmental failure. These results will provide a greatly needed mechanistic understanding of the protein complexes associated with embryogenesis and potentially uncover therapeutic targets to treat developmental failures. Moreover, the methods developed here will provide the capability to analyze virtually any biological system and thus should have broad implications for the study of many diseases.