Differential Shear Forces on Endocardial Endothelial Cells Regulate a Fibrotic Spectrum in the Left Ventricular Outflow Tract

心内膜内皮细胞上的差异剪切力调节左心室流出道中的纤维化谱

• 批准号: 10170409
• 负责人: KATHRYN JANE GRANDE-ALLEN
• 金额: $ 52.07万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170409
• 关键词: Accounting; Address; Adult; Anatomy; Anesthesia procedures; Automobile Driving; Back; Bioreactors; Blood flow; Cardiac; Cardiopulmonary Bypass; Cardiovascular Diseases; Cell Communication; Cells; Characteristics; Child; Child Care; Clinical; Complex; Computer Models; Counseling; Cytokine Signaling; Data; Discrete Subaortic Stenosis; Disease; Endothelial Cells; Endothelium; Environment; Excision; Exposure to; Extracellular Matrix; Fibroblasts; Fibrosis; Functional disorder; Geometry; Growth; Heart; Human; Immune; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Left; Lesion; Liquid substance; Mediating; Membrane; Mesenchymal; Modeling; Morbidity - disease rate; Natural History; Obstruction; Operative Surgical Procedures; Organ; Pathogenesis; Pathologic Processes; Patients; Pattern; Phenotype; Prevention; Procedures; Proteomics; Quality of life; Recurrence; Repeat Surgery; Role; Signal Transduction; Sternotomy; System; Testing; Tissues; Translating; Vascular Endothelial Cell; Ventricular; aortic valve; cellular transduction; congenital heart disorder; cost; data modeling; dynamic system; follow-up; heart function; improved; inflammatory milieu; innovation; insight; mechanical force; mechanotransduction; predictive modeling; pressure; prognostic model; response; shear stress; theories; tool

PROJECT SUMMARY Discrete subaortic stenosis (DSS) is a congenital or acquired condition that accounts for ~10% of all cases of left ventricular outflow tract (LVOT) obstruction, and is characterized by a ring of fibrous tissue below the aortic valve. Current treatment is surgical removal of the obstruction, but the unpredictable recurrence and progression of DSS leads to multiple repeat surgeries and attendant morbidity into adulthood. Current theories postulate that altered LVOT geometry causes increased shear stress and ultimately fibrosis in DSS; however, little is known about the mechanism of DSS progression. Studies in vascular endothelial cells demonstrated increased inflammation and phenotypic changes in response to altered shear forces, but effects of shear are under-studied in endocardial endothelial cells (EEC). Additionally, resident fibroblasts are implicated in organ fibrosis, including cardiac tissue, in response to altered cytokine signaling and mechanical forces. We hypothesize that that altered shear forces induce an inflammatory response by EEC, which interacts with cardiac fibroblasts (CF) to govern a fibrotic phenotype that contributes to the pathophysiology of DSS, which we will address with three specific aims. AIM 1. Elucidate the mechanisms of how shear forces regulate EEC inflammatory phenotype.First, we shall utilize patient echo data and computational modeling to develop a bioreactor that resembles altered flows in DSS. Using this innovative system, we will then test the role of CD-31 mechanosensory signaling in EEC in response to altered shear forces and geometry. Lastly, we shall investigate the effects of altered shear forces on EEC interactions with inflammatory cells in propagating a pro-inflammatory environment. AIM 2. Determine EEC transduction of altered shear forces to govern fibrosis in the LVOT. We shall investigate EEC propensity towards endoMT in response to simulated DSS altered shear and immune cell interactions. We shall then investigate the direct and inflammatory-mediated effects of EEC mechanosensing on CF that produce a fibrotic ECM. Lastly, we shall study the effect of the stiffer environment induced by fibrosis on EEC-CF crosstalk, which may propagate the fibrotic response. AIM 3. Characterize the aggressive DSS phenotype using patient data to develop a predictive model. We shall first evaluate the ECM composition, remodeling profile and echo data that characterizes the aggressive forms of DSS in humans. We shall then use these data to develop a multivariate computational model that can be used to predict an aggressive phenotype, which will be validated and tested. This proposal will improve the care of children with DSS. With completion of these aims, innovative tools and new knowledge will emerge about the effects of shear force on EEC-CF and EEC-immune cell cross-talk. These findings have potential implications for any cardiovascular disease with altered flow associated with fibrosis.

项目概要 离散性主动脉瓣下狭窄 (DSS) 是一种先天性或后天性病症，约占所有病症的 10% 左心室流出道 (LVOT) 阻塞的病例，其特征是纤维组织环 主动脉瓣下方。目前的治疗方法是手术切除阻塞，但不可预测 DSS 的复发和进展导致多次重复手术和随之而来的发病率 成年期。目前的理论假设改变 LVOT 几何形状会导致剪切应力增加， 最终导致 DSS 纤维化；然而，人们对 DSS 进展的机制知之甚少。研究于 血管内皮细胞表现出炎症增加和表型变化 改变了剪切力，但剪切力对心内膜内皮细胞（EEC）的影响尚未得到充分研究。 此外，常驻成纤维细胞参与器官纤维化，包括心脏组织，响应 改变细胞因子信号传导和机械力。我们假设剪切力的改变会导致 EEC 的炎症反应，它与心脏成纤维细胞 (CF) 相互作用以控制纤维化 表型有助于 DSS 的病理生理学，我们将通过三个具体目标来解决这个问题。 目的 1. 阐明剪切力如何调节 EEC 炎症表型的机制。首先，我们 应利用患者回波数据和计算模型来开发类似于改变流量的生物反应器 在决策支持系统中。使用这个创新系统，我们将测试 CD-31 机械感觉信号在 EEC 中的作用 对改变的剪切力和几何形状的响应。最后，我们将研究改变剪切力的影响 关于 EEC 与炎症细胞在传播促炎症环境中的相互作用。 目标 2. 确定改变剪切力的 EEC 转导以控制 LVOT 中的纤维化。我们将 研究 EEC 对 endMT 的倾向，以响应模拟 DSS 改变的剪切力和免疫 细胞相互作用。然后我们将研究 EEC 的直接影响和炎症介导的影响 CF 上的机械传感产生纤维化 ECM。最后，我们要研究一下刚性的影响 纤维化引起的环境对 EEC-CF 串扰的影响，可能会传播纤维化反应。 目标 3. 使用患者数据来表征侵袭性 DSS 表型，以开发预测模型。我们 应首先评估 ECM 成分、重塑轮廓和表征侵略性的回波数据 人类 DSS 的形式。然后，我们将使用这些数据来开发一个多元计算模型，该模型可以 用于预测攻击性表型，并将对其进行验证和测试。 该提案将改善对 DSS 儿童的护理。完成这些目标后，创新 关于剪切力对 EEC-CF 和 EEC-免疫细胞的影响的工具和新知识将会出现 相声。这些发现对任何血流改变的心血管疾病都有潜在影响 与纤维化有关。

项目成果

Computational Assessment of Valvular Dysfunction in Discrete Subaortic Stenosis: A Parametric Study.

离散主动脉瓣下狭窄瓣膜功能障碍的计算评估：参数研究。

• 发表时间: 2021-12
• 作者: Shar, Jason A;Keswani, Sundeep G;Grande;Sucosky, Philippe
• 通讯作者: Sucosky, Philippe

Impact of Aortoseptal Angle Abnormalities and Discrete Subaortic Stenosis on Left-Ventricular Outflow Tract Hemodynamics: Preliminary Computational Assessment.

主动脉间隔角异常和离散主动脉瓣下狭窄对左心室流出道血流动力学的影响：初步计算评估。

• 发表时间: 2020
• 作者: Shar, Jason A;Brown, Kathleen N;Keswani, Sundeep G;Grande;Sucosky, Philippe
• 通讯作者: Sucosky, Philippe

Significance of aortoseptal angle anomalies to left ventricular hemodynamics and subaortic stenosis: A numerical study.

主动脉间隔角异常对左心室血流动力学和主动脉瓣下狭窄的意义：一项数值研究。

• 发表时间: 2022-07
• 影响因子: 7.7
• 作者: Shar, Jason A;Keswani, Sundeep G;Grande;Sucosky, Philippe
• 通讯作者: Sucosky, Philippe

The Immune and Inflammatory Basis of Acquired Pediatric Cardiac Disease.

获得性小儿心脏病的免疫和炎症基础。

• 发表时间: 2021
• 作者: Jui, Elysa;Singampalli, Kavya L;Shani, Kevin;Ning, Yao;Connell, Jennifer P;Birla, Ravi K;Bollyky, Paul L;Caldarone, Christopher A;Keswani, Sundeep G;Grande
• 通讯作者: Grande

Association for Academic Surgery/Society of University Surgeons research awards are highly successful in fostering future surgeon-scientists.

学术外科协会/大学外科医生协会的研究奖项在培养未来的外科医生科学家方面取得了巨大成功。

• 发表时间: 2023-08
• 影响因子: 3.8
• 作者: Olutoye 2nd, Oluyinka O;Lee, Taylor;Degala, Anjali;Mueller, Jessica L;Goldstein, Allan M;Keswani, Sundeep G;Cheng, Lily S
• 通讯作者: Cheng, Lily S