Beta-catenin in vascular homeostasis and remodeling

β-连环蛋白在血管稳态和重塑中的作用

• 批准号: 9884555
• 负责人: Nicholas E Sibinga
• 金额: $ 56.25万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884555
• 关键词: Acetylation; Adult; Affect; Antineoplastic Agents; Arterial Fatty Streak; Arterial Injury; Arteries; Atherosclerosis; Blood Circulation; Blood Vessels; C-terminal; Cause of Death; Cell Death; Cell Proliferation; Cell Survival; Cells; Complex; Defect; Development; Disease; Drug Controls; Embryo; Embryonic Development; Endothelial Cells; Genes; Genetic Models; Goals; Growth; Homeostasis; Impairment; Intervention; Investments; Knowledge; Link; Malignant Neoplasms; Mediator of activation protein; Modeling; Molecular; Mus; Mutation; Neuraxis; Obstruction; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Play; Process; Protein p53; Proteins; Publishing; Reporting; Role; Safety; Signal Transduction; Smooth Muscle Myocytes; Structure; TP53 gene; Testing; Therapeutic; Tissues; Tumor Suppressor Proteins; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; Vascular remodeling; Work; atherogenesis; base; beta catenin; cell growth; histone acetyltransferase; in vivo; inhibitor/antagonist; interest; novel; novel therapeutics; organ growth; response to injury; restenosis; therapeutic target; vascular injury

Canonical Wnt/beta-catenin (β-ctn) signaling plays a crucial role in embryonic development and homeostasis of many adult tissues. Conditional inactivation of β-ctn, the sole downstream mediator of pathway activity, demonstrates its necessity in multiple diverse processes in vivo. Inactivation of β-ctn in endothelial cells (ECs), for example, yields embryonic vascular defects limited to the central nervous system, while systemic vascular development appears normal. Interestingly, our recent studies show that inactivation of β-ctn in vascular smooth muscle cells (SMCs) in mice causes death by embryonic day (E) 12.5, with systemic arteries that are dilated and incompetent due to impaired SMC proliferation, survival, and investment of the developing vascular wall. Thus during development, SMCs of the systemic circulation require β-ctn expression, while corresponding ECs do not. Our mechanistic analysis indicates that the former effect depends in part on critical signals from the β-ctn C-terminal domain that suppress acetylation and activity of the tumor suppressor p53. β-ctn functions in the adult vasculature and its potential roles in vascular homeostasis or remodeling are not well understood. Our preliminary studies indicate that SMC β-ctn can be inactivated in the adult mouse without immediate vascular consequences, but that neointimal formation after vascular injury is significantly reduced by its absence. How β-ctn inhibition affects adult vascular integrity, response to injury, and atherosclerosis has not been reported. These gaps in our understanding are significant, because aberrant β-ctn signaling has been implicated in the pathogenesis of multiple cancers, and thus inhibition of β-ctn serves as a potentially important target in several emerging anti-neoplastic strategies. This proposal encompasses three aims: first, to determine how β-ctn suppresses SMC p53 activity, second, to assess β-ctn structural and N- vs C-terminal signaling functions in vascular homeostasis, injury response, and atherosclerosis, and third, to test Wnt/β-ctn inhibition as a potential therapeutic strategy for control of accelerated vascular remodeling and/or atherosclerosis. Analysis of β-ctn in vascular function is relevant to understanding how new therapies based on Wnt/β-ctn inhibition may affect vascular homeostasis, and should allow us to evaluate the safety of such approaches and their potential utility in treatment of vascular disease.

经典 Wnt/β-连环蛋白 (β-ctn) 信号在胚胎发育过程中发挥着至关重要的作用 许多成人组织的发育和稳态。 β-ctn 有条件失活， 途径活性的唯一下游介体，证明了其在多个方面的必要性 体内不同的过程。内皮细胞 (EC) 中 β-ctn 的失活，例如， 产生仅限于中枢神经系统的胚胎血管缺陷，而全身性的 血管发育正常。有趣的是，我们最近的研究表明 小鼠血管平滑肌细胞 (SMC) 中 β-ctn 失活导致小鼠死亡 胚胎日 (E) 12.5，由于以下原因，全身动脉扩张且功能不全 SMC 增殖、存活和发育中的血管壁的投资受损。 因此，在发育过程中，体循环的 SMC 需要 β-ctn 表达， 而相应的 EC 则没有。我们的机制分析表明，前者 效果部分取决于来自 β-ctn C 末端结构域的关键信号，该信号抑制 肿瘤抑制因子 p53 的乙酰化和活性。 β-ctn 在成人脉管系统中的功能及其在血管稳态或中的潜在作用 改造还不是很了解。我们的初步研究表明 SMC β-ctn 可以在成年小鼠中失活而不会立即产生血管后果，但是 血管损伤后的新内膜形成因它的缺失而显着减少。 β-ctn 抑制如何影响成人血管完整性、对损伤的反应以及 动脉粥样硬化尚未见报道。我们的理解上的这些差距是巨大的， 因为异常的 β-ctn 信号传导与多种疾病的发病机制有关 癌症，因此抑制 β-ctn 可作为多种癌症的潜在重要靶点 新兴的抗肿瘤策略。该提案包含三个目标：第一， 确定 β-ctn 如何抑制 SMC p53 活性，其次评估 β-ctn 结构和 N 端与 C 端信号传导在血管稳态、损伤反应和 动脉粥样硬化，第三，测试 Wnt/β-ctn 抑制作为潜在的治疗策略 用于控制加速血管重塑和/或动脉粥样硬化。 血管功能中 β-ctn 的分析有助于了解新疗法如何发挥作用 基于 Wnt/β-ctn 抑制可能会影响血管稳态，并且应该允许我们 评估这些方法的安全性及其在治疗血管疾病中的潜在效用 疾病。