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Exploring Wnt-Fzd signaling specificities

探索 Wnt-Fzd 信号传导特异性

基本信息

批准号：
10810026
负责人：
KARL H WILLERT
金额：
$ 1.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10810026
关键词：
Address Adopted Agonist Animals Anterior Biochemical Biological Cell Communication Cells Clinical Complex Congenital Abnormality Defect Development Developmental Process Disease Embryo Embryonic Development Engineering Event Evolution Exhibits FZD1 gene Family Generations Goals Heart Homeostasis Human In Vitro Individual Laboratories Life Malignant Neoplasms Methods Mus Organ Organism Organoids Output Pathway interactions Population Property Reagent Research Role Signal Transduction Specific qualifier value Specificity Stem Cell Research Technology Testing Therapeutic Tissue Engineering Tissues WNT Family Gene WNT Signaling Pathway Wnt proteins cell type cellular engineering experimental study human pluripotent stem cell in vivo innovative technologies mammalian genome mimetics novel therapeutics receptor side effect stem cell self renewal stem cells tool tool development

项目摘要

Project Summary/Abstract: Cell-cell communication lies at the heart of evolution of multi-cellular life: cells send specific signals to instruct their neighbors to adopt fates distinct of their own. An important class of developmental signals is encoded by the Wnt gene family. Wnt proteins interact with their cognate receptors of the Frizzled (Fzd) family to control countless developmental processes, from establishing the polarity of a single cell within a tissue to specifying the anterior-posterior body axis of an organism. Deregulation of Wnt signaling can have catastrophic consequences, including embryonic lethality, birth defects, and disease. 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. Over the past years, we have made important contributions to the development of Wnts as research-grade reagents to manipulate human pluripotent stem (hPS) cells and generate cell populations with potential therapeutic value. However, significant challenges need to be addressed before the full potential of Wnts as therapeutics can be realized. In particular, despite their potent activities, many Wnt proteins remain difficult to isolate in a biologically active and stable form. Furthermore, with 19 Wnts and over 20 Wnt receptors (including Fzd1-10, Lrp5/6, Ror1/2, etc.) encoded in the mammalian genome, it is unclear how signaling specificity is established. Finally, many current attempts to target Wnt signaling in clinical settings are highly non-specific and produce complications and adverse side effects. The goal for the next five years is to leverage an innovative technology developed in our laboratory that utilizes engineered Wnt agonists, called Wnt mimetics, which exhibit superior biochemical properties compared to native Wnt proteins. These Wnt mimetics will be tested for their effects in several settings, including hPS cell self-renewal and differentiation, organoid cultures and in whole animals (mice). Furthermore, the proposed research will explore a new paradigm for how Wnt signaling specificity is established in vivo, and thereby enable the development of tools and approaches that pinpoint individual Wnt signaling pathways. These experiments will allow us to test our hypothesis that selective engagement and activation of individual Wnt receptors and receptor complexes trigger distinct signaling outputs and biological effects. 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/摘要：细胞间通信是多细胞生命进化的核心：细胞发送特定信号来指示他们的邻居采取了与自己不同的命运。一类重要的发育信号是由 Wnt 基因家族。 Wnt 蛋白与卷曲 (Fzd) 家族的同源受体相互作用来控制无数的发育过程，从建立组织内单个细胞的极性到指定有机体的前后体轴。 Wnt 信号传导的放松管制可能会带来灾难性的后果后果，包括胚胎致死、出生缺陷和疾病。凭借其多样化且有效的活动在发育和干细胞中，Wnt 蛋白作为细胞和组织工程的有效工具具有广阔的前景。我们研究的长期目标是更好地了解 Wnt 蛋白及其下游信号事件影响细胞命运决定，从而推进技术和治疗专门针对 Wnt 信号传导。这些年来，我们为国家发展做出了重要贡献。开发 Wnts 作为研究级试剂来操纵人类多能干 (hPS) 细胞和产生具有潜在治疗价值的细胞群。然而，还需要应对重大挑战在 Wnts 作为治疗药物的全部潜力得以实现之前就需要解决这个问题。特别是，尽管它们具有强大的然而，许多 Wnt 蛋白仍然难以以具有生物活性和稳定的形式分离出来。此外，哺乳动物编码19个Wnt和超过20个Wnt受体（包括Fzd1-10、Lrp5/6、Ror1/2等）基因组，目前尚不清楚信号特异性是如何建立的。最后，目前许多针对 Wnt 的尝试临床环境中的信号传导高度非特异性，会产生并发症和不良副作用。未来五年的目标是利用我们实验室开发的创新技术，该技术利用工程化的 Wnt 激动剂，称为 Wnt 模拟物，与天然 Wnt 蛋白。这些 Wnt 模拟物将在多种环境中测试其效果，包括 hPS 细胞自我更新和分化、类器官培养和整个动物（小鼠）。此外，拟议的研究将探索如何在体内建立 Wnt 信号特异性的新范例，从而能够开发精确定位个体 Wnt 信号通路的工具和方法。这些实验将使我们能够检验我们的假设，即个体 Wnt 的选择性参与和激活受体和受体复合物触发不同的信号输出和生物效应。拟议的研究将通过以下方式显着推进干细胞研究和组织工程领域建立新的工具和方法来在体外和体内操纵 Wnt 信号传导。凭借其丰富的角色人类紊乱和疾病，更好地了解 Wnt 信号传导对于发展针对目前无法治愈的疾病的新疗法。