Studies of Wnt Receptor interaction with agonists and antagonists

Wnt 受体与激动剂和拮抗剂相互作用的研究

• 批准号: 8248357
• 负责人: Xi He
• 金额: $ 15.59万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248357
• 关键词: Address; Agonist; Anterior; Applications Grants; Binding; Biochemical; Biological Process; Cell Differentiation process; Cell Proliferation; Cell membrane; Cell physiology; Cell surface; Complementary DNA; Complex; Defect; Degenerative Disorder; Development; Disease; Embryo; Embryonic Development; Exhibits; Family; Gene Expression; Genes; Genetic Transcription; Growth Factor; Head; Health; Hereditary Disease; Homeostasis; Homologous Gene; Human; Human Biology; Integral Membrane Protein; Invertebrates; LDL-Receptor Related Proteins; Ligands; M15; Malignant Neoplasms; Molecular; Mucous Membrane; Mutate; Mutation; Natural regeneration; Nature; Osteoporosis; Pathway interactions; Pattern; Protein Family; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Spemann' s Organizer; Therapeutic Agents; Tissues; Vertebrates; Wnt proteins; Work; Xenopus; base; cDNA Expression; cancer therapy; cell growth; extracellular; human disease; insight; member; novel; programs; receptor; receptor function; research study; somitogenesis; success; therapeutic development; xenopus development

DESCRIPTION (provided by applicant): Wnt proteins are secreted signaling molecules that regulate many fundamental aspects of cellular functions in embryogenesis and tissue homeostasis. Deregulated Wnt signaling has been implicated in many human diseases such as cancer, osteoporosis and degenerative disorders. The study of the mechanisms of Wnt signaling has critical importance for understanding basic biology and human health. Wnt signaling is initiated by two types of transmembrane receptors that constitute the Wnt receptor complex. One is a member of the Frizzled (Fz) family of serpentine receptors, while the other is a single transmembrane receptor belonging to the LDL receptor related protein (LRP) family, LRP5 or LRP6. In addition to Wnt proteins, many distinct extracellular ligands appear to engage the Fz and/or LRP5/6 receptors and activate or inhibit Wnt signaling during embryonic development and under pathological conditions. The relationships between these Wnt agonists/antagonists with Fz and LRP5/6 receptors remain poorly understood, and are the focus of this application. Three related aims for formulated. Aim1 is to study R-spondin proteins, a novel family of agonists that activate Wnt signaling. R-spondin proteins have roles in vertebrate embryogenesis and are mutated in hereditary diseases. R-spondin proteins are also being developed as cancer therapeutic agents. But the relationships among R-spondin, Wnt and Fz-LRP5/6 receptors are debated and unresolved. Experiments are proposed to address these issues and to identify additional Rspo-binding factors/receptors. Aim 2 is to study the mechanism and function of a novel transmembrane protein, M15, that inhibits Wnt/2-catenin signaling. We have performed a functional cDNA expression screen in Xenopus embryos for genes that promote anterior formation. We identified a novel transmembrane protein, termed M15, that functions as a potent Wnt antagonist. M15 exhibits specific expression in the Spemann's organizer and also during somitogenesis. We propose experiments to study the molecular mechanism of M15 in inhibition of Wnt signaling and the biological function of in head/anterior development and somite formation. Aim 3 is to study M15L function and to identify additional novel cDNAs involved in anterior-posterior patterning. M15- like (M15L) is the other member of the M15 family we identified in Xenopus and human. It is a Wnt antagonist and has head-inducing activity in Xenopus embryos, but exhibits noticeable difference in Wnt inhibition specificity compared to M15. We plan to study the expression and function of M15L and uncover similar and/or distinct roles of M15 and M15L during Xenopus development. Additionally, based on our success with the isolation of M15, we plan to continue a more comprehensive functional cDNA expression screen for other novel genes that are involved in anterior-posterior patterning. These molecular and embryological experiments together will likely advance our understanding of the regulation of the Wnt receptor complex by novel agonists and antagonists in vertebrate development and human diseases. PUBLIC HEALTH RELEVANCE: Cell growth and differentiation are regulated by the interaction between extracellular signaling molecules and their receptors on the cell surface. Defects in this interaction often cause human cancers and diseases. This proposal aims to understand the molecular nature of the interaction between a key family of signaling molecules and their receptors that have been associated with many diseases.

描述（由申请人提供）：Wnt蛋白是分泌的信号分子，可调节胚胎发生和组织稳态中细胞功能的许多基本方面。失控的Wnt信号传导与许多人类疾病有关，例如癌症，骨质疏松症和退化性疾病。对Wnt信号传导机制的研究对于理解基本生物学和人类健康至关重要。 Wnt信号传导由构成Wnt受体复合物的两种类型的跨膜受体启动。一种是蛇纹石受体的毛躁（FZ）家族的成员，而另一个是属于LDL受体相关蛋白（LRP）家族，LRP5或LRP6的单个跨膜受体。除Wnt蛋白外，许多不同的细胞外配体似乎与FZ和/或LRP5/6受体接合，并在胚胎发育和病理条件下激活或抑制Wnt信号。这些Wnt激动剂/拮抗剂与FZ和LRP5/6受体之间的关系仍然很少了解，并且是该应用的重点。三个相关的制定目标。 AIM1是研究R-Spondin蛋白，这是一种激活Wnt信号传导的新型激动剂家族。 R-Spondin蛋白在脊椎动物的胚胎发生中具有作用，并在遗传性疾病中突变。 R-Spondin蛋白也作为癌症治疗剂开发。但是R-Spondin，Wnt和Fz-LRP5/6受体之间的关系是辩论和未解决的。提出了实验来解决这些问题并确定其他RSPO结合因子/受体。 AIM 2是研究新型跨膜蛋白M15的机理和功能，该蛋白抑制Wnt/2-catenin信号传导。我们已经在Xenopus Embryos中进行了功能性cDNA表达筛选，以促进前部形成的基因。我们确定了一种称为M15的新型跨膜蛋白，该蛋白充当有效的Wnt拮抗剂。 M15在Spemann的组织者以及在体内发生过程中表现出特定的表达。我们提出了研究M15的分子机制，以抑制Wnt信号传导以及头部/前发育和节点形成的生物学功能。 AIM 3是研究M15L功能，并确定参与前后图案的其他新型cDNA。 M15-like（M15L）是我们在Xenopus and Human中确定的M15家族的另一个成员。它是一种Wnt拮抗剂，在爪蟾胚胎中具有诱导头部活性，但与M15相比，Wnt抑制特异性的差异很明显。我们计划研究M15L的表达和功能，并发现在Xenopus发育过程中M15和M15L的相似和/或不同作用。此外，基于我们在M15的隔离下的成功，我们计划继续对其他参与前后形式的新型基因进行更全面的功能性cDNA表达筛选。这些分子和胚胎学实验可能会共同提高我们对脊椎动物发育和人类疾病中新型激动剂和拮抗剂对Wnt受体复合物调节的理解。公共卫生相关性：细胞生长和分化受细胞外信号分子与其受体在细胞表面的相互作用的调节。这种相互作用的缺陷通常会导致人类癌症和疾病。该建议旨在了解关键信号分子家族与其受体与许多疾病相关的受体之间相互作用的分子性质。