Molecular Mechanisms Regulating and Interpreting BMP Signaling

调节和解释 BMP 信号转导的分子机制

• 批准号: 9894047
• 负责人: Jun Liu
• 金额: $ 5.87万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894047
• 关键词: Animals; Biochemical; Bone Morphogenetic Proteins; Caenorhabditis elegans; Cardiovascular Diseases; Cell surface; Cells; Complex; Coupled; Development; Disease; Ensure; Funding; Genetic Screening; Hereditary Disease; Human; Imaging Techniques; Ligands; Malignant Neoplasms; Membrane; Mesoderm; Molecular; Molecular Genetics; National Institute of General Medical Sciences; Pathway interactions; Play; Positioning Attribute; Process; Proteins; Reagent; Regulation; Research; Resolution; Role; Signal Pathway; Signaling Protein; Specificity; System; Time; Transforming Growth Factors; Universities; cell type; disease-causing mutation; experience; extracellular; flexibility; genome editing; high resolution imaging; in vivo; insight; novel; protein phosphatase inhibitor-2; spatiotemporal; therapeutic target; tissue/cell culture; tool; trafficking

PROJECT SUMMARY/ABSTRACT Molecular mechanisms regulating and interpreting BMP signaling Bone morphogenetic proteins (BMPs) belong to the transforming growth factor  (TGF) superfamily of ligands and the BMP signaling pathway plays roles in multiple developmental and homeostatic processes. Malfunction of the pathway causes many somatic and hereditary disorders in humans, including cardiovascular diseases and cancer. Thus multiple levels of regulation must exist in vivo to ensure proper spatiotemporal specificity, level, and duration of BMP signaling in the right cellular context. We have developed a novel, highly specific and sensitive genetic screen in C. elegans that has allowed the identification of multiple new and evolutionarily conserved modulators of the BMP pathway. These modulators span from extracellular secreted proteins, to cell surface integral membrane or GPI-anchored proteins, to proteins involved in intracellular trafficking, highlighting many levels of regulation on BMP signaling. Excitingly, several of these factors have not been previously implicated in regulating BMP signaling in any systems. In addition to the regulators, we have also identified a cell type specific target of BMP signaling in the C. elegans postembryonic mesoderm. Determining how the BMP modulators function in regulating BMP signaling and how BMP signaling is interpreted in specific cellular contexts are the research focuses under this MIRA. We propose to use a multifaceted approach that combines molecular genetic, genome editing, biochemical and high- resolution imaging techniques to dissect the functions of the BMP modulators in C. elegans. At the same time, we are also branching out to determine the functions of these factors in mammalian tissue culture cells. Our research has been funded by NIGMS since 2002 when I first set up my lab at Cornell University. Over the years, we have made substantial progress and have generated a set of tools/reagents that put us in a unique position to carry out our proposed research. Our experiences and expertise, coupled with the flexibility offered by the MIRA mechanism to pursue new research opportunities as they arise, will allow us to make sustained progress in our research. Our studies are bound to provide important insights into the complex and intricate mechanisms regulating and interpreting BMP signaling at single cell resolution in a multicellular living animal. They may also provide potential therapeutic targets for the different diseases caused by mutations in the BMP pathway.

项目摘要/摘要 调控和解释BMP信号的分子机制 骨形态发生蛋白属于转化生长因子(转化生长因子)超家族配体 BMP信号通路在多种发育和动态平衡过程中发挥作用。故障 在人类中引起许多躯体和遗传性疾病，包括心血管疾病 和癌症。因此，体内必须存在多种水平的调控，以确保适当的时空特异性， 在正确的细胞环境中BMP信号的水平和持续时间。我们已经开发出一种新奇的，高度具体的 在线虫中的敏感基因筛选，允许识别多个新的和进化的 保守的骨形态发生蛋白途径的调节因子。这些调节剂的范围从细胞外分泌的蛋白质到 细胞表面完整膜或GPI锚定蛋白，到参与细胞内运输的蛋白， 强调了对BMP信号的多个层面的监管。令人兴奋的是，这些因素中有几个并没有 此前曾参与调节任何系统中的BMP信号。除了监管机构，我们还 在线虫胚胎后中胚层中发现了BMP信号的细胞类型特异性靶点。确定 BMP调节器如何在调节BMP信号中发挥作用，以及BMP信号如何被具体解释 蜂窝语境是MIRA下的研究重点。我们建议使用多方面的方法， 结合了分子遗传学、基因组编辑、生化和高分辨率成像技术来解剖 线虫BMP调节子的功能。与此同时，我们也在扩大范围，以确定 这些因子在哺乳动物组织培养细胞中的作用。我们的研究得到了NIGMS的资助 自从2002年我第一次在康奈尔大学建立我的实验室以来。多年来，我们取得了实质性进展。 并产生了一套工具/试剂，使我们处于开展我们拟议的研究的独特地位。 我们的经验和专业知识，再加上米拉机制提供的灵活性，以追求新的 当研究机会出现时，将使我们的研究取得持续的进展。我们的研究是 一定会为调节和解释BMP的复杂和错综复杂的机制提供重要的见解 在多细胞活体动物中以单细胞分辨率发送信号。它们还可能提供潜在的治疗作用 针对骨形态发生蛋白途径突变引起的不同疾病的靶点。