Molecular mechanisms modulating BMP signaling

调节 BMP 信号传导的分子机制

• 批准号: 8630486
• 负责人: Jun Liu
• 金额: $ 29.42万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630486
• 关键词: Adolescent; Affect; Animals; Axon; Binding; Biological Models; Bone Morphogenetic Proteins; Caenorhabditis elegans; Cardiovascular Diseases; Cell Culture System; Cell surface; Cells; Cleaved cell; DCC gene; Development; Disease; Disintegrins; Dissection; Ensure; Family; Genetic Screening; Glycosphingolipids; Heart; Hemochromatosis; Hereditary Disease; Homologous Gene; Human; Iron Overload; Lead; Life; Ligands; Malignant Neoplasms; Mammals; Mediating; Membrane Microdomains; Metalloproteases; Modeling; Molecular; Molecular Genetics; Mutation; Nematoda; Organism; Pathway interactions; Peptide Hydrolases; Play; Process; Proteins; Regulation; Resolution; Role; Signal Pathway; Signal Transduction; Testing; Transforming Growth Factors; base; cell motility; design; disease-causing mutation; extracellular; human PHEMX protein; in vivo; insight; mutant; neogenin; novel; protein function; public health relevance; receptor; spatiotemporal; therapeutic target; tool; trafficking

PROJECT SUMMARY/ABSTRACT 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 mechanisms must exist to ensure proper spatiotemporal control of BMP signaling in the right cellular context. We are using the free-living nematode, C. elegans, as a model system to dissect the molecular mechanism modulating BMP signaling in vivo. C. elegans, with its wealth of genetic and molecular tools and the availability of the entire lineage, provides an excellent model system to study the functions and modulation of BMP signaling during the development of an intact organism at single cell resolution. We have developed a novel and efficient genetic screen that has allowed the identification of factors specifically modulating the BMP-like Sma/Mab signaling pathway in C. elegans. We have demonstrated that the single C. elegans RGM protein DRAG-1 acts at the ligand-receptor level to positively modulate Sma/Mab signaling. We have also discovered that the C. elegans neogenin homolog UNC-40 functions by directly binding to DRAG-1 to promote Sma/Mab signaling and that this function is separable from its function in axon and cell migration. Our screen has also uncovered a role for a conserved tetraspanin molecule TSP-21 and glycosphingolipids (GSLs) in promoting Sma/Mab signaling, providing the first in vivo evidence for the involvement of tetraspanins-enriched membrane microdomains in modulating TGF¿ signaling. Finally, our mutant screen also indicated the presence of additional "novel factors" functioning in the Sma/Mab pathway. Further identification of the corresponding proteins and mechanistic dissection on how these proteins function in modulating Sma/Mab signaling will provide important insights into the molecular mechanisms involved in regulating BMP signaling in developing animals in vivo. They may also provide potential therapeutic targets for the different diseases caused by mutations in the BMP pathway.

项目总结/摘要 骨形态发生蛋白（BMPs）属于转化生长因子。 (TGF）配体超家族和BMP信号通路在多个 发育和自我平衡过程。这条通路的故障导致许多 人类的躯体和遗传性疾病，包括心血管疾病， 癌因此，必须存在确保BMP的适当时空控制的机制 在正确的细胞环境中发出信号。我们使用自由生活的线虫C。优雅， 作为一个模型系统，以剖析调节BMP信号的分子机制， vivo. C.线虫，其丰富的遗传和分子工具和可用性， 整个谱系，提供了一个很好的模型系统，研究功能和调制 BMP信号在一个完整的有机体在单细胞分辨率的发展。 我们开发了一种新颖有效的遗传筛查，可以让 特异性调节BMP样Sma/Mab信号通路的因子的鉴定 in C.优美的我们已经证明，单一的C。线虫RGM蛋白DRAG-1 在配体-受体水平起作用以正向调节Sma/Mab信号传导。我们还 发现C. elegans neogenin homolog factors通过直接结合 与DRAG-1结合以促进Sma/Mab信号传导，并且该功能与其 在轴突和细胞迁移中起作用。我们的屏幕还揭示了一个角色， 保守的四跨膜蛋白分子TSP-21和鞘糖脂（GSL）在促进 Sma/Mab信号传导，提供了第一个体内证据， 富含四跨膜蛋白的膜微区在调节TGF β信号传导中的作用。最后， 我们的突变体筛选还表明存在额外的“新因子”在其中发挥作用。 Sma/Mab途径。进一步鉴定相应的蛋白质， 对这些蛋白质如何在调节Sma/Mab信号传导中起作用的机制进行了剖析 将为调节BMP所涉及的分子机制提供重要见解 在发育中的动物体内的信号传导。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。