Studies of Wnt Antagonists

 描述（由申请人提供）：脂蛋白分泌型Wnt家族的信号传导调节胚胎发生和组织稳态的许多基本方面。Wnt信号传导失调与出生缺陷、癌症、骨质疏松症和退行性疾病等人类疾病有关。因此，Wnt信号传导机制的研究对于理解基础生物学和人类健康以及潜在的疾病治疗至关重要。除了Wnt蛋白之外，已经发现分泌的和膜结合的Wnt激动剂和拮抗剂的不同家族在胚胎发育期间以及在生理或病理条件下增强或抑制Wnt信号传导。这些Wnt调节剂以阶段和/或组织特异性方式调节Wnt信号输出，并且通常是Wnt通路控制的多种功能的基础，并且它们代表了Wnt相关发病机制的潜在治疗靶点。非洲爪蟾胚胎是发现和鉴定脊椎动物胚胎发生中许多Wnt调节剂家族的有力模型系统。基于我们之前在这一领域的成功，本次更新申请将重点关注两个Wnt拮抗剂家族的机制和功能。目的1是研究Tiki蛋白，一种新的Wnt失活酶，我们发现，是非洲爪蟾前图案所需的。Tiki是第一个通过酶失活Wnt信号传导抑制的例子。 配体，并代表了一个新的金属蛋白酶家族的创始成员，这是保守的致病菌到人类。我们将描述Tiki酶功能，Wnt切割特异性及其在调节不同Wnt信号通路中的机制。目的2和目的3是研究另一种保守的Wnt拮抗剂在非洲爪蟾胚胎发育中的分子基础和生物学功能。这种Wnt拮抗剂的作用机制尚未完全了解，将在目标2中使用常规和先进的分子和生物化学技术进行研究。基于我们的研究结果，Wnt拮抗剂在母源和非洲爪蟾胚胎的卵裂和原肠胚形成阶段表达，其在不同发育阶段调节Wnt介导的背腹和前后图案的潜在作用将在目的3中进行研究。这些分子和胚胎学实验将可能为Wnt信号调控和脊椎动物胚胎发生提供新的见解。

 DESCRIPTION (provided by applicant): Signaling by the secreted Wnt family of lipoproteins regulate many fundamental aspects of embryogenesis and tissue homeostasis. Deregulated Wnt signaling has been implicated in human diseases including birth defects, cancer, osteoporosis and degenerative disorders. The study of the mechanisms of Wnt signaling thus has critical importance for understanding basic biology and human health, and for potential disease treatment. In addition to Wnt proteins, distinct families of secreted and membrane-bound Wnt agonists and antagonists have been found that enhance or inhibit Wnt signaling during embryonic development and in physiological or pathological conditions. These Wnt modulators regulate Wnt signaling output in stage- and/or tissue-specific manner and often underlie diverse functions that Wnt pathways control, and they represent potential therapeutic targets for Wnt-related pathogenesis. The Xenopus embryo has been a powerful model system for the discovery and characterization of many families of Wnt modulators in vertebrate embryogenesis. Building on our previous success in this area, this renewal application will focus on the mechanisms and functions of two families of Wnt antagonists. Aim 1 is to study the Tiki protein, a novel Wnt-inactivating enzyme that we identified and is required for Xenopus anterior patterning. Tiki is the first example of Wnt signaling inhibition through enzymatic inactivation of the ligand, and represents the founding member of a new metalloprotease clan that is conserved from pathogenic bacteria to human. We will characterize Tiki enzymatic function, Wnt cleavage specificity, and its mechanism in regulating different Wnt signaling pathways. Aim 2 and Aim 3 are to study the molecular basis and biological functions of another conserved Wnt antagonist during Xenopus embryogenesis. The mechanism by which this Wnt antagonist operates is not fully understood, and will be investigated in Aim 2 using conventional and advanced molecular and biochemical techniques. Based on our findings that the Wnt antagonist is expressed maternally and during cleavage and gastrulation stages of Xenopus embryos, its potential roles in regulating Wnt-mediated dorsoventral and anteroposterior patterning in different developmental stages will be investigated in Aim 3. These molecular and embryological experiments together will likely provide novel insights into Wnt signaling regulation and vertebrate embryogenesis.