TGFb Signaling in Vertebrate Mesoderm Induction

脊椎动物中胚层诱导中的 TGFb 信号转导

• 批准号: 7247938
• 负责人: ALI H BRIVANLOU
• 金额: $ 31.18万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247938
• 关键词: Activins; Address; Adult; Amaze; Bilateral; Biochemical; Biological; Biological Assay; C-terminal; Caenorhabditis elegans; Cell Line; Cell Nucleus; Cells; Cocos; Complement Factor B; Development; Disease; Dorsal; Embryo; Embryonic Development; Event; Family; Family member; Funding; Gastrula; Generations; Genes; Germ Layers; Goals; Human; Individual; Knowledge; Life; Malignant Neoplasms; Mammalian Cell; Mesoderm; Molecular; Mutation; Neurula; OS4 Gene; Organogenesis; Pathway interactions; Pattern; Phosphoric Monoester Hydrolases; Phosphorylation Site; Proteins; Rana; Range; Side; Signal Pathway; Signal Transduction; Snow; Staging; Structure; Substrate Specificity; TGFB1 gene; Tissues; Transforming Growth Factors; Vertebrates; Xenopus; angiogenesis; base; carboxy-terminal domain phosphatase; cell type; developmental disease; expression cloning; in vivo; loss of function; member; neurogenesis; notochord; research study; tumorigenesis; zygote

DESCRIPTION (provided by applicant): The overall goal of this proposal is to elucidate the biochemical and embryological function of the Transforming Growth Factor-B (TGF-B) pathway in the induction and patterning of the mesodermal embryonic germ layer in Xenopus. By combining expression cloning in Xenopus embryos, global transcriptional profiling, and biochemical approaches during the last round of funding, we have identified key factors which modulate the TGF-B pathway at multiple levels in the generation of the primary embryonic axis and the establishment of discrete cell fates. Building on this progress, we will focus on two of these factors that are unusual regulators of the TGFB pathway: Coco, acting outside of the cell, and SCP2, the first identified Smad phosphatase, acting in the nucleus. I have two main objectives. The first is to dissect the molecular mechanism underlying the biochemical function of coco in the context of the very early embryo. This will be done by eliminating Coco from the fertilized eggs and assess the consequence of this loss of function on the development of the embryo. In line with this mechanistic analysis, embryonic factors that interact with Coco protein will be identified to unveil Coco-partners. The second aim, targets the unraveling of the biochemical, cellular and embryological function of long awaited players in the TGFB pathway, Smad phosphatases, which we have finally identified. We will also extend this analysis to individual family members of this group by addressing comparatively their biochemical and embryological functions. The TGFB pathway has been evolutionarily conserved from C. elegans to human, covering an amazing range of biological activities both in embryogenesis and adult life. Mutations in this pathway are the causes of various diseases including developmental disorders and human cancer. Therefore, the findings derived from the studies presented in this application extend beyond their relevance to our basic molecular understanding of embryological events, and reach our knowledge about this important signaling pathway, reiterated again and again in different tissues and cell type throughout life.

描述（由申请人提供）：该提案的总体目标是阐明转化生长因子-B（TGF-B）途径的生物化学和胚胎学功能在Xenopus中中胚层胚胎生殖层的诱导和模式中。通过将表达克隆在最后一轮资金中组合，全局转录分析和生化方法，我们已经确定了关键因素，这些因素可以在主要胚胎轴的生成中调节TGF-B途径在多个水平上，并建立了离散细胞命运。在这一进展的基础上，我们将重点关注这些因素中的两个因素，这些因素是TGFB途径的异常调节剂：可可，在细胞外发作，而SCP2（首先鉴定出的Smad磷酸酶）作用于细胞核中。我有两个主要目标。首先是在非常早期的胚胎中剖析可可的生化功能的分子机制。这将通过从受精卵中消除可可来完成，并评估这种功能丧失对胚胎发展的结果。与这种机械分析一致，将确定与可可蛋白相互作用的胚胎因子以揭示可可合伙人。第二个目标是针对TGFB途径中已久的玩家Smad磷酸酶的生化，细胞和胚胎学功能的解散，我们终于确定了。我们还将通过解决相对的生化和胚胎学功能来扩展该分析的单个家庭成员。从秀丽隐杆线虫到人类，TGFB途径在进化上是保守的，涵盖了胚胎发生和成人生活中的惊人生物学活性。该途径中的突变是各种疾病的原因，包括发育障碍和人类癌症。因此，从本应用中提出的研究中得出的发现超出了它们与我们对胚胎学事件的基本分子理解的相关性，并在整个生命中一次又一次地在不同的组织和细胞类型中重申了我们对这一重要信号通路的了解。