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TRPC4-mediated calcium signals accelerate vascular remodeling in pulmonary arterial hypertension

TRPC4介导的钙信号加速肺动脉高压的血管重塑

基本信息

批准号：
10201722
负责人：
CHRISTOPHER MICHAEL FRANCIS
金额：
$ 15.95万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201722
关键词：
Animals Area Arteries Atherosclerosis Award Biology Blood Vessels Blood capillaries Calcium Calcium Signaling Cell Proliferation Cessation of life Chronic Computer Models Development Disease Disease Progression Education Endothelial Cells Endothelium Environment Equipment Etiology Family Frequencies Functional disorder Gap Junctions Geometry Goals Heart failure Human Resources Ion Channel Laboratories Lead Lesion Link Lung Mediating Mediator of activation protein Membrane Mentors Microcirculation Morbidity - disease rate Patients Pattern Permeability Physiological Physiology Production Protein Isoforms Proteins Pulmonary Hypertension Pulmonary Pathology Pulmonary Vascular Resistance Pulmonary artery structure Quality of life Research Resistance Role Severities Signal Pathway Signal Transduction Site Source Systolic Pressure Testing Therapeutic Time Training Trees Vascular Diseases Vascular Proliferation Vascular remodeling Vascular resistance Vasodilator Agents Ventricular Work arterial remodeling artery occlusion career design hemodynamics improved member mortality neglect novel pressure pulmonary arterial hypertension receptor response shear stress skills vasoconstriction

项目摘要

Abstract Pulmonary arterial hypertension (PAH) is an incurable disease of elevated pulmonary artery pressure that culminates in death due to right heart failure. The etiology of PAH is comprised of increased vasoconstriction in resistance arteries and remodeling of the arterial microcirculation. All current therapies for PAH target vasoconstriction, but patient survival has not improved because remodeling remains irreversible. Thus, there has been considerable impetus to determine the mediators of remodeling in PAH. Members of the transient receptor potential (TRP) family ion channels have been implicated as drivers of vascular proliferation and remodeling in PAH. Our lab has shown that TRPC4, a subtype of the canonical TRP family, increases mortality and vascular lesion number and severity in PAH. A separate mechanism of hemodynamic perturbations resulting in turbulent or oscillatory endothelial shear stress has also been associated with increased vascular resistance and remodeling in PAH. Given that both TRPC4 and shear-induced signals are linked by the nexus of intracellular calcium, we hypothesize that TRPC4 and shear-mediated endothelial calcium signals will exacerbate lesion formation in PAH. Therefore, the goal of this proposal is to determine the interaction between TRPC4-dependent endothelial calcium signals and oscillatory shear stress as a driver of occlusive remodeling in PAH. Determining the underlying basis of vascular remodeling in PAH may lead to a novel class of PAH therapeutics for extending patient survival and improving quality of life. As a candidate trained in the quantitative areas of computational modeling and animal physiology at the Center for Lung Biology, I am well suited to investigate the determinants of vascular remodeling in PAH. Furthermore, the goals of this award are aligned with my specific career goals of gaining research expertise, education, and professional skills on my path to career independence. The proposed research plan takes advantage of the robust institutional environment and considerable expertise in the pathophysiology of PAH. The project mentor, Dr. Troy Stevens, and additional personnel are well known experts in the fields of endothelial biology, vascular physiology, and pulmonary hypertension. Additionally, our state-of-the-art laboratories have the requisite equipment to complete this work.

摘要肺动脉高压（PAH）是一种肺动脉压力升高的不治之症，最终死于右心衰竭PAH的病因包括血管收缩增加，阻力动脉和动脉微循环重塑。PAH目标的所有当前治疗血管收缩，但患者的生存率没有改善，因为重塑仍然是不可逆的。因此已成为确定PAH重塑介质的重要推动力。临时人员受体电位（TRP）家族离子通道被认为是血管增殖的驱动因素， PAH中的重塑。我们的实验室已经表明，TRPC 4，典型的TRP家族的亚型，增加 PAH的死亡率和血管病变数量及严重程度。血液动力学的一种独立机制导致湍流或振荡内皮剪切应力的扰动也与 PAH的血管阻力和重塑增加。假设TRPC 4和剪切诱导信号通过细胞内钙离子的联系，我们假设TRPC 4和剪切介导的内皮细胞钙信号将加剧PAH中的损伤形成。因此，本提案的目标是确定 TRPC 4依赖的内皮钙信号和振荡剪切应力之间的相互作用作为一个驱动因素， PAH中的闭塞性重构。确定PAH中血管重构的基础可能导致用于延长患者生存期和改善生活质量的新型PAH治疗剂。作为候选人在计算建模和动物生理学的定量领域接受过培训，生物学方面，我非常适合研究PAH中血管重塑的决定因素。此外，目标这个奖项是符合我的具体职业目标，获得研究专业知识，教育，专业技能在我职业独立的道路上。拟议的研究计划利用了强大的机构环境和PAH病理生理学方面的大量专业知识。项目导师，博士Troy Stevens和其他人员都是内皮生物学、血管内皮细胞生物学和血管内皮细胞生物学领域的知名专家。生理学和肺动脉高压。此外，我们最先进的实验室拥有必要的设备来完成这项工作。