Maximizing Investigators' Research Award (R35 - Clinical Trial Optional)

最大化研究者研究奖（R35 - 临床试验可选）

• 批准号: 10596608
• 负责人: ETHAN LEE
• 金额: $ 56.27万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596608
• 关键词: Adult; Agonist; Award; Behavior; Biochemical; Biological Process; Cell Maintenance; Cells; Clinical Trials; Colorectal Cancer; Compensation; Complex; Defect; Development; Disease; Drug Targeting; Embryonic Development; FDA approved; Familial Adenomatous Polyposis Syndrome; Genetic Transcription; Goals; Human; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutation; Nuclear; Orphan Drugs; Pathway interactions; Pharmaceutical Preparations; Play; Proteins; Receptor Activation; Regulation; Research; Research Personnel; Role; Signal Transduction; System; Tumor Suppressor Proteins; WNT Signaling Pathway; Work; Xenopus; adult stem cell; cancer initiation; egg; mathematical model; mutant; premalignant; protein purification; receptor; reconstitution; small molecule inhibitor; stem cells; ubiquitin isopeptidase; ubiquitin-protein ligase

PROJECT SUMMARY: The evolutionarily conserved Wnt pathway plays a critical role during metazoan development and stem cell maintenance in the adult. Mutations in the Wnt pathway leading to its misregulation in humans have been shown to contributes to both developmental defects and cancers. In the latter case, over 90% of all non-hereditary forms of colorectal cancers are initiated by mutations in the Wnt pathway leading to its inappropriate activation. There are no FDA-approved drugs that inhibit the Wnt pathway, which is likely due to our incomplete understanding of the mechanism of Wnt signaling and the lack of suitable drug targets. The primary focus of my lab is to understand the biological function of the Wnt signaling pathway by deciphering its molecular mechanism and identifying new Wnt components. Our ultimate goal is to use this information to understand how deregulation of the Wnt pathway can lead to Wnt- driven diseases in humans. Over more than a decade, my lab has made significant contributions to our fundamental understanding of Wnt signaling. These breakthroughs were accomplished via the development of the first biochemical system (using Xenopus egg extract), the reconstitution of active purified proteins, the development of the first mathematical model (Lee-Heinrich model), and the identification of small molecule inhibitors (CK1 agonists), one of which has been designated by the FDA as an orphan drug for a familial precancerous disease (familial adenomatous polyposis). Our current work focused on determining the role of the USP46/UAF1/WDR20 deubiquitinase complex in regulating LRP6 receptor turnover, the mechanism by which APC regulates Wnt receptor activity, the role of the -catenin degradation complex in mediating bistable pathway behavior, and the roles of USP47 and STK38, in regulating Wnt signaling. In our renewal application, we now propose to 1) reconstitute LRP6 ubiquitylation and identify its evolutionarily conserved E3 ligase, 2) understand the basis for signal compensation upon Wnt receptor loss in APC mutant cells, 3) provide evidence for the role of bistability in generating morphogenetic signaling, and 4) uncover the roles of the STK38 and TRIP12 in nuclear Wnt signaling.

项目概要： 进化上保守的Wnt通路在后生动物发育过程中发挥着关键作用 和成人干细胞维持。 Wnt 通路的突变导致其 人类的失调已被证明会导致发育缺陷和 癌症。在后一种情况下，超过 90% 的非遗传性结直肠癌是 由 Wnt 通路中的突变引发，导致其不适当的激活。没有 FDA 批准的抑制 Wnt 通路的药物，这可能是由于我们的不完整 对Wnt信号传导机制的了解以及缺乏合适的药物靶点。这 我实验室的主要重点是通过以下方式了解 Wnt 信号通路的生物学功能： 破译其分子机制并鉴定新的 Wnt 成分。我们的最终目标是 使用此信息来了解 Wnt 通路的放松管制如何导致 Wnt- 人类的驱动疾病。 十多年来，我的实验室为我们的基础研究做出了重大贡献 了解 Wnt 信号传导。这些突破是通过开发实现的 第一个生化系统（使用爪蟾卵提取物），活性纯化的重构 蛋白质、第一个数学模型（Lee-Heinrich 模型）的发展以及 小分子抑制剂（CK1α激动剂）的鉴定，其中一种已被指定为 FDA 认定为治疗家族性癌前疾病（家族性腺瘤）的孤儿药 息肉病）。 我们目前的工作重点是确定 USP46/UAF1/WDR20 去泛素酶的作用 调节 LRP6 受体转换的复合物，APC 调节 Wnt 的机制 受体活性，-连环蛋白降解复合物在介导双稳态通路中的作用 行为以及 USP47 和 STK38 在调节 Wnt 信号传导中的作用。在我们的更新中 应用程序，我们现在建议 1) 重建 LRP6 泛素化并从进化角度识别其 保守的 E3 连接酶，2) 了解 Wnt 受体丢失时信号补偿的基础 APC 突变细胞，3) 为双稳定性在生成形态发生中的作用提供了证据 信号传导，4) 揭示 STK38 和 TRIP12 在核 Wnt 信号传导中的作用。