Chemically assisted remodeling of infarcted heart tissue by targeting Wnt lipidation

7.项目摘要/摘要 分泌的Wnt信号分子对细胞命运的协调是必不可少的 多细胞生物体的决策。尽管他们在广泛的 一系列疾病，包括癌症和退行性疾病，Wnt分子和 它们调节的细胞反应在很大程度上对选择性化学物质是不敏感的。 操纵。在过去的几年里，我的研究小组在 努力确定WNT相关疾病的新的化学干预点。我们的 发现Wnt酰基转移酶豪猪(PORCN)具有高度的可药性和 WNT介导的通信中的化学漏洞开辟了新的方法 实现再生医学目标的前提是调节Wnt信号。在这 提案中，我们概述了对PORCN的发展至关重要的实验 作为心肌梗死后使用的一流抗纤维化药物的抑制剂。 这些研究将勾勒出支持再生的机制基础 PORCN抑制剂的活性，并确定最优给药方案，使 延长化学物质暴露时间，最大限度地提高心脏组织的再生效果。数据 完成这些研究后回国将有助于制定更多 使用Wnt通路拮抗剂促进成人组织生长的一般手册 再生。

7. Project Summary/Abstract The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision-making in multicellular organisms. Despite their impressive role in a broad range of maladies including cancer and degenerative diseases, Wnt molecules and the cellular responses that they regulate have largely been refractory to selective chemical manipulation. In the last few years, my research group has taken a leadership role in efforts to identify novel points of chemical intervention in Wnt-related diseases. Our discovery that the Wnt acyltransferase Porcupine (Porcn) is highly druggable and a chemical vulnerability in Wnt-mediated communication has laid open new approaches to achieving regenerative medicine goals premised upon modulating Wnt signaling. In this proposal, we outline experiments that are essential to the development of Porcn inhibitors as first-in-class anti-fibrotic agents for use following myocardial infarction. These studies will delineate the mechanistic basis underlying the pro-regenerative activity of Porcn inhibitors and define an optimal drug delivery regiment that minimizes chemical exposure time and maximizes regenerative outcome in heart tissue. The data returned from the completion of these studies will facilitate the development of a more general playbook for the use of Wnt pathway antagonists in promoting adult tissue regeneration.