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: 10543170
• 负责人: Jun Liu
• 金额: $ 52.01万
• 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 2024-01-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543170
• 关键词: Animals; Binding; 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; Postembryonic; Process; Protein Secretion; 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 (BMP) 属于转化生长因子  (TGF) 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 该途径会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， 在正确的细胞环境中 BMP 信号传导的水平和持续时间。我们开发了一种新颖的、高度具体的 对秀丽隐杆线虫进行灵敏的遗传筛选，可以鉴定多种新的和进化的 BMP 途径的保守调节剂。这些调节剂涵盖从细胞外分泌蛋白到 细胞表面整合膜或 GPI 锚定蛋白，到参与细胞内运输的蛋白质， 强调了 BMP 信号传导的多层次监管。令人兴奋的是，其中一些因素尚未得到解决 以前涉及调节任何系统中的 BMP 信号传导。除了监管机构之外，我们还 确定了秀丽隐杆线虫胚胎后中胚层中 BMP 信号传导的细胞类型特异性靶标。确定 BMP 调制器如何发挥调节 BMP 信号传导的作用以及 BMP 信号传导在特定情况下如何解释 细胞环境是 MIRA 的研究重点。我们建议采用多方面的方法 结合分子遗传学、基因组编辑、生化和高分辨率成像技术来解剖 线虫中 BMP 调节剂的功能。与此同时，我们也在不断拓展以确定 这些因子在哺乳动物组织培养细胞中的功能。我们的研究得到了 NIGMS 的资助 自 2002 年我第一次在康奈尔大学建立实验室以来。这些年来，我们取得了长足的进步 并生成了一套工具/试剂，使我们处于独特的地位来开展我们提出的研究。 我们的经验和专业知识，加上 MIRA 机制提供的灵活性，可以追求新的 研究机会一旦出现，将使我们能够在研究方面取得持续进展。我们的研究是 必将为调节和解释 BMP 的复杂机制提供重要见解 多细胞活体动物中单细胞分辨率的信号传导。它们还可能提供潜在的治疗作用 BMP 通路突变引起的不同疾病的靶标。