Autologous Progenitor Cells Delivery in Renovascular Disease

肾血管疾病中的自体祖细胞输送

• 批准号: 7591820
• 负责人: Lilach O Lerman
• 金额: $ 22.67万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591820
• 关键词: Address; Adjuvant Therapy; Angiography; Angioplasty; Architecture; Atherosclerosis; Autologous; Balloon Angioplasty; Blood Vessels; Cardiovascular system; Cells; Chronic; Chronic Kidney Failure; Data; Deterioration; Development; Diagnostic; Disease; End stage renal failure; Endothelium; Epithelial; Epithelial Cells; Etiology; Experimental Models; Family suidae; Functional disorder; Healed; Image; Imaging Techniques; In Situ; In Vitro; Individual; Injury; Intervention; Kidney; Light; Measures; Medicine; Microcirculation; Modeling; Morbidity - disease rate; Morphology; Organ; Outcome; Oxidation-Reduction; Pathogenesis; Patients; Perfusion; Physiological; Play; Procedures; Recovery; Renal Artery Stenosis; Renal function; Renovascular Hypertension; Role; Simulate; Stem cells; Structure; System; Techniques; Testing; Therapeutic; Tissues; Tubular formation; Vascular Diseases; Western World; Work; Wound Healing; X-Ray Computed Tomography; cell injury; design; healing; hemodynamics; improved; improved functioning; in vivo; injured; kidney vascular structure; mortality; neovascularization; novel; novel strategies; novel therapeutics; patient population; peripheral blood; public health relevance; repaired; response; success

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.

描述（由申请人提供）：在西方世界，血管疾病对发病率和死亡率的影响呈上升趋势。动脉粥样硬化性肾动脉狭窄 (ARAS) 是慢性肾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的不可逆损伤，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策略尚未确定，但迫切需要。该提议的工作假设是补充自体祖细胞 (APC) 将恢复肾细胞完整性并改善 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新型单侧 ARAS 猪模型中进行测试，使用我们为研究单肾功能和结构而改进的独特成像方法。 APC将从外周血中分离出来，在体外扩增，然后结合肾血管造影或经皮腔内肾血管成形术（PTRA）注入狭窄肾脏，纵向研究它们对单肾血流动力学、功能、挑战反应和恢复潜力的影响。体内研究将与肾微循环原位 3D 结构、肾氧化还原状态以及 APC 处理和未处理肾脏形态的体外表征相关。我们新的初步数据表明，APC 改善了缺血肾脏的功能和结构，证明了这种方法赋予肾脏保护的可行性。这些研究将追求两个具体目标。具体目标 1 将检验补充 APC 将改善 ARAS 肾脏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 后立即和同一过程中通过肾内输送 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。拟议的研究可能会极大地增进我们对 ARAS 肾损伤发病机制的理解，并建立一种新颖的、临床上可行的治疗策略。此外，它们可以帮助制定策略来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。拟议的研究可能会增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，并帮助修复肾血管和其他细胞）改善这种疾病的肾脏结果的能力。这些研究可能会为设计和指导肾血管疾病患者管理的诊断和治疗措施提供重要启示并产生重大影响。