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）信号通路在胚胎发育中起着至关重要的作用。 许多成年组织的发育和体内平衡。β-ctn的条件灭活， 唯一的下游介质的途径活动，证明了其必要性，在多个 在体内的不同过程。例如，内皮细胞（EC）中β-ctn的失活， 产生胚胎血管缺陷，仅限于中枢神经系统，而全身 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的失活导致死亡， 胚胎日龄（E）12.5，体循环动脉扩张，由于 受损的SMC增殖、存活和发育中的血管壁的投资。 因此，在发育过程中，体循环的SMC需要β-ctn表达， 而相应的EC不具有。我们的机理分析表明， 这种效应部分取决于来自β-ctn C-末端结构域的关键信号， 肿瘤抑制因子p53的乙酰化和活性。 β-ctn在成人血管系统中的功能及其在血管内稳态和血管内分泌中的作用 重塑并不容易理解。我们的初步研究表明，SMC β-ctn 可以在成年小鼠中失活，而不会立即引起血管后果， 血管损伤后新生内膜的形成因其缺失而显著减少。 β-ctn抑制如何影响成人血管完整性，对损伤的反应，以及 动脉粥样硬化尚未报道。我们理解上的这些差距是巨大的， 由于异常β-ctn信号转导与多种肿瘤的发病机制有关， 因此，β-ctn的抑制在几种癌症中充当潜在的重要靶标。 新兴的抗肿瘤策略。这项建议包括三个目标：第一， 确定β-ctn如何抑制SMC p53活性，其次，评估β-ctn的结构和 N-与C-末端信号传导功能在血管稳态，损伤反应， 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如何 基于Wnt/β-ctn抑制可能会影响血管稳态，并应允许我们 评价这些方法的安全性及其在治疗血管性 疾病