Hypoxia and inflammatory injury in human renovascular hypertension

人类肾血管性高血压的缺氧和炎症损伤

• 批准号: 9049492
• 负责人: Lilach O Lerman
• 金额: $ 56.94万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-20 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049492
• 关键词: Address; Adipose tissue; Affect; Autologous; Biopsy; Blood Vessels; Blood Volume; Blood flow; CCL2 gene; Cell Therapy; Cell surface; Cells; Characteristics; Chronic Kidney Failure; Complex; Data; Disease; Equilibrium; Evaluation; Excision; FDA approved; Fibrosis; Health; Histologic; Homing; Human; Hypoxia; Immunologics; Individual; Infiltration; Inflammation; Inflammatory; Infusion procedures; Injury; Interleukin-6; Investigation; Investigational New Drug Application; Ischemia; Kidney; Kidney Diseases; Lesion; Link; Magnetic Resonance; Measurable; Measures; Mesenchymal; Mesenchymal Stem Cells; Oxidative Stress; Pathway interactions; Patient Schedules; Patients; Pattern; Phenotype; Physiological; Population; Prevalence; Prevention; Process; Recovery; Recovery of Function; Regional Blood Flow; Renal Blood Flow; Renal Replacement Therapy; Renal function; Renovascular Hypertension; Role; Severities; Signal Transduction; Stimulus; Stromal Cells; Surface; T-Lymphocyte; TNF gene; Testing; Time; Tissues; Tubular formation; Vascular Diseases; Venous; aging population; angiogenesis; arginase; blood oxygen level dependent; cardiovascular risk factor; cytokine; deoxyhemoglobin; glomerular filtration; hemodynamics; human subject; immunoregulation; inflammatory marker; kidney vascular structure; macrophage; mannose receptor; new technology; patient safety; progenitor; renal artery; repaired; restoration; safety study; stem; tissue oxygenation; tissue repair; tool

DESCRIPTION (provided by applicant): Renal injury in atherosclerotic renovascular disease (RVD) often progresses despite restoring large vessel patency. This process is linked to rarefaction of microvessels, cortical hypoxia, stimulation of inflammatory cytokines and recruitment of progenitor and inflammatory cells. Our overall hypothesis is that the severity of renal injury and recovery in human RVD will depend upon not only restoration of blood flow but also a transition from a pro-inflammatory, fibrogenic phenotype to one favorable to restoring tubular integrity that will reflect the functional balance of M1 (inflammatory) and M2 (reparative) macrophages. The specific aims in this project apply novel technologies to define cortical and medullary blood flow and oxygenation in human subjects. They will be combined with studies of kidney biopsies and renal venous cytokine patterns that can be ascribed to M1 or M2 macrophages. We propose to modify the inflammatory and angiogenic pathways by delivering intra-renal autologous adipose-derived mesenchymal stem cells (MSCs) capable of immunomodulation. Specific Aim 1 will define the relationship between cortical and medullary blood flows, tissue hypoxia, and inflammatory signals, defined by trans-renal cytokine gradients in RVD. Our hypothesis is that the level of cortical hypoxia (defined both by blood flow reduction and elevated deoxyhemoglobin) will be related to induction of inflammatory homing signals. Specific Aim 2 will undertake to modify the intrarenal microenvironment by delivery of autologous adipose-derived MSCs in advanced RVD. The hypothesis to be tested is that MSCs will result in measurable increases in glomerular filtration, cortical and medullary blood flow and oxygenation, and reduced tissue inflammation with a cytokine signature characteristic of M2 macrophages. Specific Aim 3 will combine administration of MSC's to individuals with advanced RVD undergoing renal revascularization via renal artery stenting. Our hypothesis is that MSCs combined with renal artery stenting will augment tissue repair and will better restore kidney oxygenation and function than MSCs alone. These studies will provide the first investigation in humans of the potential for cell-based therapy to augment vascular and functional repair after restoring blood flow to the kidney.

描述（由申请人提供）：尽管恢复了较大的容器通畅，但动脉粥样硬化肾血管疾病（RVD）的肾脏损伤通常会进展。该过程与微血管，皮质缺氧，炎症细胞因子的刺激以及祖细胞和炎症细胞的募集有关。我们的总体假设是，人RVD中肾脏损伤的严重程度不仅取决于血流的恢复，还取决于从促炎性的，纤维化表型的过渡到有利于恢复管状完整性的一种，这将反映M1（炎症）和M2（reparative）（reparative）（reparative）的功能平衡 巨噬细胞。该项目中的具体目的采用了新技术来定义人类受试者的皮质和髓质血流和氧合。它们将与可以归因于M1或M2巨噬细胞的肾脏活检和肾静脉细胞因子模式的研究结合使用。我们建议通过传递能够免疫调节的肾脏内自体脂肪衍生的间充质干细胞（MSC）来改变炎症和血管生成途径。具体目标1将定义皮质和髓质血流，组织缺氧和炎症信号之间的关系，这是由RVD中的跨肾脏细胞因子梯度定义的。我们的假设是，皮质缺氧的水平（通过降低血流和脱氧血红蛋白升高定义）将与诱导炎症归巢信号有关。特定的目标2将通过在高级RVD中递送自体脂肪衍生的MSC来修改果内微环境。要检验的假设是MSC将导致肾小球滤过，皮质和髓样血流以及 用M2巨噬细胞的细胞因子特征氧合和减少组织炎症。特定的目标3将通过肾动脉支架对患有肾脏血运重建的晚期RVD的个体进行管理。我们的假设是，与单独的MSC相比，MSC与肾动脉支架相结合将增强组织修复，并更好地恢复肾脏氧合和功能。这些研究将为人类提供首次研究，以恢复流入肾脏的血液后，基于细胞的治疗来增强血管和功能修复。