Cyclic stretch of bicuspid aortic valves: elucidating its implications for cell signaling and tissue mechanics.

二叶式主动脉瓣的循环拉伸：阐明其对细胞信号传导和组织力学的影响。

基本信息

批准号：
10607130
负责人：
Toni Mcclish West
金额：
$ 7.38万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607130
关键词：
3-Dimensional Actins Address Affect Age Anatomy Aortic Valve Stenosis Architecture Basal Cell Biochemical Cell Shape Cell physiology Cells Cellular Morphology Clinical Commissure Congenital Abnormality Cytoskeleton Data Development Disease Disease Progression Early Diagnosis Early identification Echocardiography Environment Ethylenes Event Exposure to Extracellular Matrix Fellowship Gel Glycols Goals Heart Valves Human Image In Situ Investigation Lead Legal patent Length Link Measures Mechanics Mediating Microscopy Modeling Morbidity - disease rate Morphology Myofibroblast Nuclear Organ Pathway interactions Patients Pattern Periodicity Persons Pharmacological Treatment Phenotype Procedures Process Proteins Proteomics Quality of life Research Research Personnel Risk Role Running Sampling Series Sex Differences Signal Transduction Smooth Muscle Stimulus Stretching System Texas Tissues Training Transforming Growth Factor beta Travel Universities Work aortic valve aortic valve disorder aortic valve replacement bicuspid aortic valve biobank biochemical model biomechanical model body system cell type conditioning effective therapy experience experimental study interstitial cell malformation mathematical model mechanical signal metaplastic cell transformation mortality negative affect novel pharmacologic response therapeutic target transcription factor treatment strategy two photon microscopy valve replacement

项目摘要

PROJECT SUMMARY: While 1.4% of people have the congenital defect of bicuspid aortic valve (BAV), BAV patients make up 50% of the patients that receive aortic valve replacements. Moreover, patients with BAVs develop aortic stenosis (AS) earlier, and thus require replacements at younger ages than patients with normal tricuspid aortic valves (TAV). Given the limited durability of replacements, BAV patients have a high procedure burden that negatively affects their length and quality of life. Therefore, development of a pharmacological therapy will reduce morbidity and mortality from AS. Our long-term goal is to understand the BAV disease process at the cellular level to develop effective treatments that mitigate AS. Since no pharmacological treatment has been forthcoming, our hypothesis is that abnormal valve interstitial cell (VIC) deformation patterns present in BAVs have a crucial role in the biochemical signaling events in AS. Since AS is associated with VIC activation into myofibroblasts and transforming growth factor-beta (TGFB) signaling, this study addresses the relationship between mechanically-conditioned cellular morphology and TGFB signaling in two specific aims: 1. Determine what parameters of mechanical conditioning experienced in varying aortic valve anatomies affect VIC morphology. The level of myofibroblast activation will first be determined in native human valve leaflet explants from BAV and TAV. The morphologies of cells from native tissues will be compared to that of cells mechanically conditioned in a novel 3D high-throughput biaxial oscillatory stretch screen (3D HT-BOSS) to determine what cyclical biaxial stretch, matrix stiffness, and VIC basal contractility is required to produce morphologies seen in BAVs and TAVs. 2. Ascertain how altering mechanical pattern will modify VIC response to TGFB. Quantitative proteomics will be employed to develop steady-state models of VIC TGFB signaling from VICs freshly isolated from native human valve leaflets. Microscopy of 3D HT-BOSS samples will then be employed to analyze shifts in: 1) EC50 of αSMA protein and 2) nuclear localization of TGFB- mediated transcription factors upon exogenous TGFB stimulation. Through this investigation, underlying drivers of AS and novel target pathways for pharmacological treatment will therefore be uncovered. Furthermore, the training that the fellowship applicant, Dr. Toni West, will receive will enable her to make the leap to becoming an independent investigator. Dr. West will be conducting research in the lab of her sponsor, Dr. Michal Sacks, and in the lab of her collaborator, Dr. Aaron Baker, at the University of Texas. As part of her training, Dr. West will travel to Columbia University, where her co- sponsor Dr. Giovanni Ferrari runs the biobank she will be collecting tissues and cells from.

项目摘要：虽然 1.4% 的人患有二叶式主动脉瓣 (BAV) 先天性缺陷， BAV 患者占接受主动脉瓣置换术的患者的 50%。使用 BAV 的患者更早出现主动脉瓣狭窄 (AS)，因此需要在更年轻的年龄进行置换术具有正常三尖瓣主动脉瓣 (TAV) 的患者鉴于置换术的耐用性有限，BAV。患者的手术负担很高，这会对他们的寿命和生活质量产生负面影响。药物治疗的发展将降低 AS 的发病率和死亡率。我们的长期目标是在细胞水平上了解 BAV 疾病过程，以开发有效的治疗方法由于目前还没有药物治疗，我们的假设是缓解 AS 的治疗方法。 BAV 中存在的异常瓣膜间质细胞 (VIC) 变形模式在 AS 中的生化信号事件与 VIC 活化成肌成纤维细胞相关。和转化生长因子-β (TGFB) 信号传导，本研究探讨了两者之间的关系机械调节细胞形态和 TGFB 信号传导有两个具体目标： 1. 确定不同主动脉瓣经历的机械调节参数解剖学影响 VIC 形态首先将确定肌成纤维细胞的活化水平。来自 BAV 和 TAV 的天然人瓣膜小叶外植体来自天然细胞的形态。组织将与在新型 3D 高通量中机械调节的细胞进行比较双轴振荡拉伸屏幕（3D HT-BOSS）确定什么是周期性双轴拉伸、矩阵刚度和 VIC 基础收缩力是产生 BAV 和 TAV 中所见形态所必需的。 2. 确定改变机械模式将如何改变 VIC 对 TGFB 的反应。蛋白质组学将用于开发 VIC TGFB 信号传导的稳态模型然后将从天然人类瓣膜小叶中新鲜分离出来的 3D HT-BOSS 样本进行显微镜检查。用于分析以下方面的变化：1) αSMA 蛋白的 EC50 和 2) TGFB- 的核定位外源TGFB刺激后介导的转录因子。通过这项研究，我们发现了 AS 的潜在驱动因素和药理学的新靶标途径因此，治疗将被揭露。此外，奖学金申请人 Toni West 博士将接受的培训将使她能够成为一名独立研究者，韦斯特博士将在该领域进行研究。她的资助者 Michal Sacks 博士的实验室和她的合作者 Aaron Baker 博士的实验室，位于作为培训的一部分，韦斯特博士将前往哥伦比亚大学，她的同事在那里赞助商乔瓦尼·法拉利博士经营着一个生物库，她将从中收集组织和细胞。