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。项目摘要/摘要 分泌的Wnt信号分子对于细胞命令的配位至关重要 多细胞生物的决策。尽管在广泛的 包括癌症和退化性疾病，Wnt分子和疾病范围 它们调节的细胞反应在很大程度上是对选择性化学的难治性的 操纵。在过去的几年中，我的研究小组在 努力确定与WNT相关疾病中化学干预的新颖点。我们的 发现Wnt酰基转移酶豪猪（Porcn）是高度可药的，A WNT介导的交流中的化学脆弱性已为 在调节WNT信号传导时实现再生医学目标。在这个 提案，我们概述了对PORCN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剂。 这些研究将描述促增再生长的机械基础 猪肉抑制剂的活性并定义一个最佳的药物输送团，以最小化 化学暴露时间并最大化心脏组织中的再生结果。数据 从完成这些研究的完成后返回将有助于进一步发展 使用WNT途径拮抗剂促进成人组织的一般剧本 再生。