Autologous Progenitor Cells Delivery in Renovascular Disease

描述（由申请人提供）：血管疾病对发病率和死亡率的影响在西方世界呈上升趋势。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，与单独的RAS相比，它会加剧肾功能的恶化。此外，通过放大内皮和上皮细胞损伤并损害血管细胞修复机制，动脉粥样硬化加剧了狭窄肾脏中的不可逆损伤并削弱了其在血管重建后恢复的能力。改善这些严重后果的适当战略尚待确定，但迫切需要。支持这一提议的工作假设是，自体祖细胞（APC）的补充将恢复肾细胞的完整性，并改善ARAS肾的功能，结构和恢复前景。这一假设将在我们开发和表征的单侧ARAS的新型猪模型中进行测试，使用我们已经改进的独特成像方法来研究单肾功能和结构。APC将从外周血中分离，在体外扩增，然后与肾血管造影术或经皮腔内肾血管成形术（PTRA）联合给予狭窄肾，以纵向研究其对单肾血流动力学、功能、对激发的反应和恢复潜力的影响。体内研究将与APC处理和未处理肾脏的肾脏微循环、肾脏氧化还原状态和形态学的原位3D结构的体外表征相关。我们的新的初步数据表明，APC改善了缺血肾脏的功能和结构，证明了这种方法对肾脏保护的可行性。这些研究将追求两个具体目标。具体目标1将检验APC补充将改善ARAS肾的基础功能和结构的假设。具体目标2将检验以下假设：在PTRA后立即和在相同手术期间通过肾内递送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。这些研究可能会大大提高我们对ARAS肾损伤发病机制的认识，并建立一个新的，临床可行的治疗策略。此外，他们可能有助于制定战略，以确定肾活力的预测因素，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管理。公共卫生相关性：目前迫切需要明确动脉粥样硬化性肾血管病损伤肾脏的机制，并制定保护肾脏的策略。这些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的能力。（其可以从个体的外周血中分离，并帮助修复肾血管和其他细胞）以改善这种疾病的肾脏结果。这些研究很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，并产生实质性的影响。

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.