Structural characterization of protein complexes involved in embryogenesis.

参与胚胎发生的蛋白质复合物的结构表征。

• 批准号: 8915540
• 负责人: Kevin Drew
• 金额: $ 5.61万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915540
• 关键词: Aortic coarctation; Binding Sites; Biochemical; Cardiovascular system; Cells; Chemicals; Cleft Palate; Collection; Complex; Computational Biology; Computational Technique; Computer Analysis; Congenital Abnormality; Data; Data Set; Defect; Development; Developmental Biology; Disease; Electron Microscopy; Embryo; Embryonic Development; Erinaceidae; Failure; Fractionation; Health Care Costs; Healthcare Systems; Homology Modeling; Human; Individual; Infant Mortality; Machine Learning; Maps; Mass Spectrum Analysis; Methods; Mind; Modeling; Molecular; Molecular Sieve Chromatography; Mus; Nervous system structure; Pathway interactions; Peptides; Process; Protein Subunits; Proteins; Proteome; Proteomics; Rana; Regulation; Role; Sea Anemones; Sea Urchins; Spinal Dysraphism; Staging; Structural Models; System; Techniques; Therapeutic; Tissues; Transforming Growth Factor beta; Uncertainty; United States; Xenopus laevis; biological systems; bone; computer studies; computerized tools; craniofacial development; crosslink; data acquisition; data mining; egg; embryo tissue; fly; infant death; insight; model building; notch protein; novel; protein complex; protein structure; public health relevance; research study; stoichiometry; structural biology; therapeutic target; three dimensional structure; tool

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.

描述(申请人提供)：出生缺陷，例如那些影响心血管系统(如主动脉缩窄)、神经系统(如脊柱裂)和头面部发育(如腭裂)的出生缺陷，是美国约20%的婴儿死亡的原因，每年给医疗保健系统带来的负担高达数十亿美元。这些缺陷通常是胚胎发育中断的结果，胚胎发育依赖于对关键通路的严格调控，包括Wnt、Hedgehog、Notch、PAR和骨形态发生肽/转化生长因子β。然而，这些途径中涉及的许多蛋白质复合体缺乏详细的分子特征，还有更多的有待发现。专注于胚胎组织的大规模蛋白质组学工作正开始系统地识别大量的蛋白质。利用这些数据，我建议开发新的方法来从结构和功能上表征与胚胎发生相关的蛋白质复合体。具体地说，我将开发新的计算工具(I)用于最近相互作用(即蛋白质亚复合体)的数据挖掘以及(Ii)计算蛋白质化学计量。然后，我将整合这些信息，以建立结构模型，既能表征单个复杂的功能，又能确定它们在发育失败中的作用。这些结果将提供对与胚胎发生相关的蛋白质复合体的迫切需要的机械理解，并可能发现治疗发育障碍的治疗靶点。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影响。