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: 9507901
• 负责人: Nicholas E Sibinga
• 金额: $ 60.42万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 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 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9507901
• 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; Injury; 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; 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

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.

典型的Wnt/β-catenin（β-CTN）信号传导在胚胎中起着至关重要的作用 许多成人组织的发育和稳态。 β-CTN的条件失活， 途径活动的唯一下游介体在多个中证明了它的必要性 体内各种过程。例如，内皮细胞中β-CTN的失活（EC），例如 产生胚胎血管缺陷限于中枢神经系统，而全身性 血管发育似乎正常。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的失活导致死亡 胚胎日（E）12.5，由于全身性动脉，由于 发育中的血管壁的SMC增殖，生存和投资受损。 因此，在发育过程中，全身循环的SMC需要β-CTN表达， 虽然相应的EC却没有。我们的机械分析表明前者 效果部分取决于来自抑制β-CTN C末端结构域的关键信号 肿瘤抑制p53的乙酰化和活性。 β-CTN在成年血管中起作用及其在血管稳态中的潜在作用 重塑尚未很好地理解。我们的初步研究表明SMCβ-CTN 可以在成年小鼠中失活而不会立即导致血管后果，但是 血管损伤后的新内膜形成显着降低了其缺失。 β-CTN抑制如何影响成人血管完整性，对损伤的反应和 尚未报道动脉粥样硬化。我们理解中的这些差距很大， 因为在多个的发病机理中隐含了异常的β-CTN信号传导 癌症，因此抑制β-CTN是几种潜在的重要目标 新兴的反塑性策略。该提案包括三个目标：首先 确定β-CTN如何抑制SMC p53活性，其次，以评估β-CTN结构和 N-与C末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抑制作用作为潜在的治疗策略 控制加速的血管重塑和/或动脉粥样硬化。 血管功能中β-CTN的分析与了解新疗法的方式有关 基于Wnt/β-CTN抑制作用可能会影响血管稳态，应使我们能够 评估这种方法的安全性及其在血管治疗的潜在效用 疾病。