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）：本提案的总体目标是阐明转化生长因子-B (TGF-B) 途径在非洲爪蟾中胚层胚胎胚层诱导和模式化中的生化和胚胎学功能。通过在上一轮融资中结合非洲爪蟾胚胎中的表达克隆、全局转录分析和生化方法，我们已经确定了在初级胚胎轴的生成和离散细胞的建立中在多个水平上调节 TGF-B 途径的关键因素。细胞的命运。在这一进展的基础上，我们将重点关注其中两个作为 TGFB 途径异常调节因子的因子：在细胞外起作用的 Coco，以及在细胞核中起作用的第一个被识别的 Smad 磷酸酶 SCP2。我有两个主要目标。首先是在非常早期的胚胎背景下剖析可可生化功能背后的分子机制。这将通过从受精卵中去除可可并评估这种功能丧失对胚胎发育的影响来完成。根据这一机制分析，将鉴定与 Coco 蛋白相互作用的胚胎因子，以揭开 Coco 伙伴的面纱。第二个目标是解开我们最终确定的 TGFB 途径中期待已久的参与者 Smad 磷酸酶的生化、细胞和胚胎功能。我们还将通过比较其生化和胚胎学功能，将这种分析扩展到该群体的各个家庭成员。 TGFB 途径从秀丽隐杆线虫到人类在进化上都是保守的，涵盖了胚胎发生和成年生活中一系列令人惊奇的生物活性。该途径的突变是多种疾病的原因，包括发育障碍和人类癌症。因此，从本申请中提出的研究中得出的结果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，并达到了我们对这一重要信号传导途径的了解，该信号传导途径在整个生命过程中的不同组织和细胞类型中一次又一次地重复。