Autologous Progenitor Cells Delivery in Renovascular Disease

描述(申请人提供)：在西方世界，血管疾病对发病率和死亡率的影响正在上升。动脉粥样硬化性肾动脉狭窄(ARAS)是慢性肾脏疾病和肾血管性高血压的常见病因，与单独使用RAS相比，它会加剧肾功能的恶化。此外，动脉粥样硬化通过放大内皮和上皮细胞损伤和损害血管细胞修复机制，加剧了狭窄肾脏的不可逆转损伤，并削弱了其在血运重建后恢复的能力。改善这些严重后果的适当战略尚未确定，但迫切需要。支持这一建议的工作假设是，补充自体祖细胞(APC)将恢复肾脏细胞的完整性，并改善ARAS肾脏的功能、结构和恢复前景。这一假设将在我们开发和表征的一种新的单侧ARAS猪模型中进行验证，使用我们改进的独特的成像方法来研究单肾的功能和结构。APC将从外周血中分离、体外扩增，然后结合肾血管造影或经皮腔内肾血管成形术(PTRA)注入狭窄的肾脏，纵向研究它们对单肾血流动力学、功能、对挑战的反应和恢复潜力的影响。体内研究将与APC治疗和未治疗肾脏的原位3D结构、肾脏氧化还原状态和形态的体外特征相关联。我们新的初步数据显示，APC改善了缺血肾脏的功能和结构，证明了这种方法在提供肾脏保护方面的可行性。这些研究将追求两个具体目标。具体目标1将检验补充APC将改善ARAS肾脏基本功能和结构的假设。具体目标2将验证这样一个假设，即在PTRA后立即和在相同的过程中，通过肾内注射APC来增强细胞修复，将改善ARAS肾脏对干预的反应，并恢复其恢复潜力。这些研究可能极大地促进我们对ARAS肾损伤发病机制的理解，并建立一种新的、临床可行的治疗策略。此外，它们可能有助于制定策略，以确定肾脏生存能力的预测因素，并提高治疗的成功率。因此，这些研究可能有助于动脉粥样硬化和肾血管疾病患者的治疗。公共卫生相关性：迫切需要确定动脉粥样硬化性肾血管疾病损害肾脏的机制，并制定保护肾脏的策略。拟议的研究可能会促进我们对肾损伤发病机制的理解，并将确定自体祖细胞(可以从个体的外周血中分离出来，帮助修复肾血管和其他细胞)改善这种疾病的肾脏预后的能力。这些研究可能为设计和指导肾血管疾病患者的诊断和治疗措施提供重要的启示和实质性的分支。

DESCRIPTION (provided by applicant): The impact of vascular disease on morbidity and mortality is on the rise in the Western world. Atherosclerotic renal artery stenosis (ARAS), a common etiology of chronic kidney disease and renovascular hypertension, amplifies deterioration of renal function compared to RAS alone. Furthermore, by amplifying endothelial and epithelial cell injury and impairing vascular cellular repair mechanisms, atherosclerosis exacerbates irreversible damage in the stenotic kidney and blunts its ability to recover following revascularization. Adequate strategies to improve these grave outcomes are yet to be identified, but are in dire need. The working hypothesis underlying this proposal is that replenishment of autologous progenitor cells (APC) would restore renal cellular integrity and improve the function, structure, and recovery prospects of the ARAS kidney. This hypothesis will be tested in a novel pig model of unilateral ARAS that we have developed and characterized, using unique imaging approaches that we have refined to study single-kidney function and structure. APC will be isolated from peripheral blood, expanded in vitro, and then administered into the stenotic kidney in conjunction with renal angiography or percutaneous transluminal renal angioplasty (PTRA), to study longitudinally their effects on single-kidney hemodynamics, function, response to challenge, and recovery potential. The in vivo studies will be correlated with in vitro characterization of the in situ 3D architecture of the renal microcirculation, renal redox status, and morphology in APC-treated and -untreated kidneys. Our new preliminary data show that APC improved the function and structure of the ischemic kidney, demonstrating the feasibility of this approach to confer renal protection. These studies will pursue 2 specific aims. Specific Aim 1 will test the hypothesis that replenishment of APC would improve the basal function and structure of the ARAS kidney. Specific Aim 2 will test the hypothesis that enhancing cellular repair by intra-renal delivery of APC, immediately after PTRA and during the same procedure, would improve the response of the ARAS kidney to intervention and restore its recovery potential. The proposed studies may greatly advance our understanding of the pathogenesis of renal injury in ARAS, and establish a novel, clinically feasible therapeutic strategy. Furthermore, they may assist in development of strategies to identify predictors of renal viability and improve the success of treatment. Thus, these studies may contribute towards management of patients with atherosclerosis and renovascular disease. PUBLIC HEALTH RELEVANCE: There is a pressing need to define the mechanisms by which atherosclerotic renovascular disease damages the kidney, and develop strategies to protect it. The proposed studies may advance our understanding of the pathogenesis of renal injury, and will determine the ability of autologous progenitor cells (which can be isolated from the individual's peripheral blood, and help repair renal vascular and other cells) to improve renal outcomes in this disease. These studies are likely to shed important light into and have a substantial ramification for designing and directing diagnostic and therapeutic measures for management of patients with renovascular disease.