Molecular Mechanisms Regulating and Interpreting BMP Signaling

项目概要/摘要 调节和解释BMP信号传导的分子机制 骨形态发生蛋白（BMPs）属于转化生长因子β（TGF β）配体超家族 BMP信号通路在多种发育和稳态过程中发挥作用。故障 这一途径导致人类许多躯体和遗传性疾病，包括心血管疾病 和癌症因此，体内必须存在多个水平的调节以确保适当的时空特异性， 水平和持续时间的BMP信号在正确的细胞环境。我们发明了一种新颖的， 和敏感的遗传筛选。它允许识别多种新的和进化上 BMP途径的保守调节剂。这些调节剂从细胞外分泌蛋白， 细胞表面整合膜或GPI锚定蛋白，涉及细胞内运输的蛋白， 突出了BMP信号传导的多个调节水平。令人兴奋的是，这些因素中有几个没有被 以前参与调节BMP信号在任何系统。除了监管机构，我们还 确定了C.胚后中胚层。确定 BMP调节剂如何在调节BMP信号传导中起作用，以及BMP信号传导如何在特定的 细胞环境是本MIRA的研究重点。我们建议采用多方面的办法， 结合分子遗传学、基因组编辑、生物化学和高分辨率成像技术， C.优雅与此同时，我们也在扩大范围， 这些因子在哺乳动物组织培养细胞中的功能。我们的研究由NIGMS资助 从2002年我在康奈尔大学建立实验室开始。多年来，我们在这方面取得了实质性进展， 并生成了一套工具/试剂，使我们处于独特的位置来开展我们提议的研究。 我们的经验和专业知识，加上MIRA机制提供的灵活性， 研究机会的出现，将使我们能够在我们的研究中取得持续的进展。我们的研究是 必将为调节和解释BMP的复杂机制提供重要的见解 在多细胞活动物中以单细胞分辨率进行信号传导。它们还可能提供潜在的治疗 针对由BMP途径突变引起的不同疾病。

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.