Delineating the mechanisms underlying heart valve endothelial repair

描述心脏瓣膜内皮修复的机制

• 批准号: 10464257
• 负责人: VOLKHARD LINDNER
• 金额: $ 45.07万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464257
• 关键词: Affect; Aging; Aortic Injury; Aortic Rupture; Aortic Valve Stenosis; Cells; Childhood; Clinical; Clinical Management; Communication; Congenital Heart Defects; Congestive Heart Failure; Deterioration; Diagnosis; Disease; Endothelial Cells; Endothelium; Functional disorder; Genetic Transcription; Heart Valve Diseases; Heart Valves; Hour; Human; Impairment; In Vitro; Individual; Infant; Injury; Lead; Left; Modeling; Molecular; Mus; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Paracrine Communication; Pathology; Patients; Pediatrics; Population; Process; Proteomics; Public Health; Reporting; Signal Transduction; Site; Testing; Therapeutic; Tissues; Treatment Step; Work; aortic valve; base; design; effective therapy; endothelial dysfunction; endothelial repair; follow-up; functional disability; histological studies; improved; in vivo; innovation; interstitial; interstitial cell; migration; mouse model; neonate; novel therapeutic intervention; prevent; repaired; response; response to injury; restoration; therapeutically effective; transcriptomics

PROJECT ABSTRACT Valvular aortic stenosis (VAS) accounts for approximately 3-6% of all congenital heart defects,1 and if left untreated can lead to congestive heart failure in neonates and young infants. Non-invasive, percutaneous balloon valvuloplasty (BVP) is the preferred first step of treatment in pediatrics with the intent to postpone definitive surgery. Outcomes show that while BVP significantly reduces aortic valve (AoV) peak gradient within the first 24 hours in the majority of patients, by the 2-3 year follow up more than half re-stenose and require surgical intervention to repair or replace the dysmorphic and failing valve.2, 3 Therefore, while BVP is favorable in some patients, others are diagnosed with poor clinical outcomes and it is not clear why. Studies report that BVP can injure or even rupture the AoV,4, 5 and studies in rabbits have shown that balloon inflation specifically injures the endothelium.6, 7 Furthermore, our work in mice strongly suggests that direct injury to, or targeted dysfunction of the valve endothelium causes structural deterioration and functional impairment of the AoV, consistent with histological studies in humans reporting poor endothelial integrity in diseased valve tissue.8-11 Taken together, these studies suggest that endothelial damage is a significant contributor of valve pathology, and this may underlie poor outcomes observed in VAS patients following BVP. This raises the question: Can restoring endothelial function be an effective therapeutic strategy to treat structural and functional deterioration of the AoV in susceptible individuals? To explore this, we developed a surgical mouse model of AoV endothelial injury that causes structural and functional deterioration. Using this model, we show that in response to injury, young healthy mice activate a beneficial intrinsic reparative response that leads to endothelial restoration, while this response is impaired in aging mice with known endothelial dysfunction.12 In addition, we propose a mechanism underlying these diverse responses. This proposal will test the overall hypothesis that: The beneficial intrinsic reparative response of the injured valve endothelium requires Tgf1- Cthrc1 signaling between valve endothelial, and underlying valve interstitial cells to promote proliferation and migration of neighboring uninjured cells, leading to endothelial restoration. To test this, we propose three specific aims: 1) Determine the cellular and molecular mechanisms involved in the beneficial intrinsic response following AoV endothelial injury; 2) Determine the requirement of endothelial-Tgf1 for the beneficial intrinsic reparative response of the injured AoV endothelium; and 3) Identify interstitial-Cthrc1 as a critical factor for the beneficial intrinsic reparative response of the injured AoV endothelium. Successful completion will define innovative mechanisms of the intrinsic reparative response as a result of AoV endothelial injury that can be applied to the therapeutic design of mechanistic-based compounds to promote endothelial restoration and prevent structural and functional deterioration, particularly in susceptible individuals.

项目摘要 主动脉瓣狭窄 (VAS) 约占所有先天性心脏病的 3-6%1，如果保留的话 未经治疗可导致新生儿和小婴儿充血性心力衰竭。 球囊瓣膜成形术 (BVP) 是儿科治疗的首选第一步，旨在推迟 结果表明，虽然 BVP 显着降低了主动脉瓣 (AoV) 的峰值梯度。 大多数患者在最初 24 小时内，到 2-3 年随访时，一半以上出现再狭窄，需要 手术干预来修复或更换畸形和衰竭的瓣膜。2, 3 因此，虽然 BVP 是有利的 在一些患者中，另一些患者被诊断出临床结果不佳，但原因尚不清楚。 研究报告称，BVP 会损伤甚至破裂 AoV,4, 5，并且对兔子的研究表明， 球囊膨胀会特别损伤内皮细胞。6, 7 此外，我们在小鼠身上的研究强烈表明： 瓣膜内皮的直接损伤或有针对性的功能障碍会导致结构恶化和功能障碍 AoV 受损，与人类组织学研究报告的内皮完整性较差一致 患病的瓣膜组织。8-11 综上所述，这些研究表明内皮损伤是一个重要的原因。 瓣膜病理学的影响因素，这可能是 BVP 后 VAS 患者观察到的不良结果的原因。 这就提出了一个问题：恢复内皮功能能否成为治疗结构性病变的有效治疗策略？ 为了探索这一点，我们开发了一种手术方法 使用该模型，我们建立了导致结构和功能恶化的 AoV 内皮损伤小鼠模型。 研究表明，为了应对损伤，年轻的健康小鼠会激活一种有益的内在修复反应，从而导致 内皮修复，而这种反应在已知内皮功能障碍的衰老小鼠中受到损害。 12 此外，我们提出了一个支持这些不同反应的机制，该提案将测试整体。 假设： 受损瓣膜内皮的有益内在修复反应需要 Tgf1- 瓣膜内皮细胞和下面的瓣膜间质细胞之间的 Cthrc1 信号传导促进增殖和 邻近未受伤细胞的迁移，导致内皮修复。 为了测试这一点，我们提出了三个具体目标：1）确定细胞和分子机制 参与 AoV 内皮损伤后的有益内在反应 2) 确定以下要求； 内皮-Tgf1 对受损 AoV 内皮细胞产生有益的内在修复反应；3) 识别 间质-Cthrc1 作为受伤 AoV 有益的内在修复反应的关键因素 内皮细胞的成功完成将定义内在修复反应的创新机制。 AoV 内皮损伤的结果可应用于基于机制的化合物的治疗设计 促进内皮修复并防止结构和功能恶化，特别是在易感人群中 个人。