Exploring Wnt-Fzd signaling specificities

探索 Wnt-Fzd 信号传导特异性

• 批准号: 10388751
• 负责人: KARL H WILLERT
• 金额: $ 20.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388751
• 关键词: Affinity; Agonist; Biochemical; Cell Surface Proteins; Cells; Collection; Congenital Abnormality; Development; Disease; Embryo; Engineering; Event; Exhibits; Fluorescence; Funding; Human; In Vitro; Libraries; Methods; Pathway interactions; Property; Publishing; Regenerative Medicine; Research; Role; Signal Transduction; Specificity; Stem Cell Research; Surface; Technology; Therapeutic; Tissue Engineering; WNT Signaling Pathway; Wnt proteins; Work; Yeasts; base; cancer therapy; cellular engineering; design; in vivo; innovative technologies; instrument; mimetics; nanobodies; novel; novel therapeutics; receptor; screening; stem cells; tool

Project Summary We are requesting funds to purchase a fluorescence-based cell sorter, the BioRad S3E, for the purpose of screening nanobody libraries and identifying and isolating high affinity binders to cell surface proteins that transduce Wnt signals. Wnt proteins represent an important class of developmental signals with diverse functions across all metazoan species. Deregulation of Wnt signaling can have catastrophic consequences, including embryonic lethality, birth defects, and disease. Specific and selective targeting of Wnt signaling has great therapeutic potential in regenerative medicine and the treatment of cancer. Additionally, with their diverse and potent activities in development and stem cells, Wnt proteins hold great promise as potent tools in cell and tissue engineering. The long-term objective of our research is to gain a better understanding of how Wnt proteins and their downstream signaling events influence cell fate decisions, and thereby advance technologies and treatments that specifically target Wnt signaling. To this end, we have developed an innovative technology that utilizes engineered Wnt agonists, called Wnt mimetics, which exhibit superior biochemical properties compared to native Wnt proteins. Using our previously developed and published Wnt mimetic, called F7L6, as a guide, we propose to develop a collection of such Wnt agonists, each designed to engage and activate distinct types of Wnt receptors. The requested instrument will enable the identification and isolation of novel high affinity binders and accelerate the development of novel Wnt mimetics. The proposed research will significantly advance the field of stem cell research and tissue engineering by establishing new tools and methods to manipulate Wnt signaling in vitro and in vivo. With its abundant roles in human disorders and diseases, a better understanding of Wnt signaling is essential for the development of novel therapies for currently incurable diseases.

项目摘要 我们正在申请资金购买一台基于荧光的细胞分选仪，BioRad S3E，用于 筛选纳米抗体文库并鉴定和分离对细胞的高亲和力结合剂的目的 抑制Wnt信号的表面蛋白。 Wnt蛋白代表了一类重要的发育信号，在不同发育阶段具有不同的功能。 所有的后生动物物种。Wnt信号的失调可能会产生灾难性的后果， 包括胚胎致死、出生缺陷和疾病。Wnt的特异性和选择性靶向 信号传导在再生医学和癌症治疗中具有巨大的治疗潜力。 此外，Wnt蛋白在发育和干细胞中具有多种有效的活性， 在细胞和组织工程中作为有效工具具有巨大的前景。 我们研究的长期目标是更好地了解Wnt蛋白和 它们的下游信号传导事件影响细胞命运决定，从而促进 专门针对Wnt信号传导的技术和治疗。为此，我们开发了 一种利用工程化Wnt激动剂的创新技术，称为Wnt模拟物， 与天然Wnt蛋白质相比具有上级生物化学性质。使用我们以前开发的 并发表了Wnt模拟物，称为F7L6，作为指导，我们建议开发一个这样的集合 Wnt激动剂，每种设计用于接合和激活不同类型的Wnt受体。的 所要求的仪器将能够鉴定和分离新的高亲和力结合剂， 加速新型Wnt模拟物的开发。 这项拟议中的研究将大大推进干细胞研究和组织领域 通过建立新的工具和方法在体外和体内操纵Wnt信号转导， vivo.由于Wnt在人类疾病中的丰富作用， 信号传导对于目前无法治愈的疾病的新疗法的开发是必不可少的。