Chemically assisted remodeling of infarcted heart tissue by targeting Wnt lipidation

通过靶向 Wnt 脂化化学辅助重塑梗塞心脏组织

• 批准号: 9364733
• 负责人: RHONDA BASSEL-DUBY
• 金额: $ 41.92万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9364733
• 关键词: Acyltransferase; Adult; Animals; COL6A1; Cardiac; Cardiac Myocytes; Cells; Cessation of life; Chemical Exposure; Chemicals; Cicatrix; Collagen; Collagen Type VI; Communication; Coronary artery; Cultured Cells; Data; Decision Making; Degenerative Disorder; Dependovirus; Deposition; Development; Disease; Drug Delivery Systems; Drug Exposure; Enzymes; Event; Fibroblasts; Fibrosis; Genes; Genetic Recombination; Genetic Transcription; Goals; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Hypertrophic Cardiomyopathy; In Vitro; Infarction; Injury; Intervention; Leadership; Ligands; Ligation; Lipids; Longevity; Malignant Neoplasms; Maps; Mediating; Mitosis; Molecular Chaperones; Mus; Myocardial Infarction; Natural regeneration; Normal tissue morphology; Organism; Outcome; Outcome Study; Participant; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Porcupines; Production; Proteins; Quality of life; Recovery; Recovery of Function; Refractory; Regenerative Medicine; Regenerative response; Research; Role; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Solid; Survivors; System; Technology; Testing; Therapeutic; Time; Tissues; United States; WNT Signaling Pathway; Wnt proteins; Wound Healing; aged; base; cardiac regeneration; cell type; chemotherapeutic agent; clinical development; commune; diagnostic biomarker; experience; experimental study; heart function; improved; improved functioning; inhibitor/antagonist; injured; innovation; next generation; novel; novel diagnostics; novel strategies; regenerative; repaired; research clinical testing; response; stem; targeted agent; tissue regeneration; wound

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.

7. 项目总结/摘要 分泌的 Wnt 信号分子对于细胞命运的协调至关重要 多细胞生物中的决策。尽管他们在广泛的领域发挥了令人印象深刻的作用 一系列疾病，包括癌症和退行性疾病、Wnt 分子和 它们所调节的细胞反应在很大程度上不受选择性化学物质的影响 操纵。在过去的几年里，我的研究小组在以下方面发挥了领导作用： 努力确定化学干预 Wnt 相关疾病的新点。我们的 发现 Wnt 酰基转移酶 Porcupine (Porcn) 具有高度药物化性和 Wnt 介导的通讯中的化学脆弱性开辟了新的方法 实现再生医学目标的前提是调节 Wnt 信号传导。在这个 提案中，我们概述了对 Pocn 发展至关重要的实验 抑制剂作为心肌梗塞后使用的一流抗纤维化药物。 这些研究将描述促再生的机制基础 Porcn 抑制剂的活性并确定最佳的药物递送方案，以最大限度地减少 化学暴露时间并最大限度地提高心脏组织的再生效果。数据 完成这些研究后的回报将有助于开发更多 使用 Wnt 通路拮抗剂促进成体组织的通用手册 再生。