Renal Vascular Injury

肾血管损伤

• 批准号: 7226092
• 负责人: KARL A. NATH
• 金额: $ 36.27万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226092
• 关键词: Bone Marrow Transplantation; Breeding; CDKN1A gene; Coagulation Process; Distant; Endothelium; Functional disorder; Funding; Genes; Inflammation; Inflammatory; Injury; Ischemia; Kidney; Knock-out; Link; Localized; Modeling; Monocyte Chemoattractant Protein-1; Mus; Mutant Strains Mice; Organ; Pathway interactions; Principal Investigator; Process; Proteins; Range; Role; Sickle Cell Anemia; Signal Transduction; Site; Stress; Thromboplastin; Tissues; Triad Acrylic Resin; Vascular blood supply; Veno-Occlusive Disease; heme oxygenase-1; hemodynamics; indexing; kidney vascular structure; mortality; oncoprotein p21; programs; renal ischemia; response; sickling

Tissue ischemia is a consequence of vaso-occlusive sickle cell disease (SCO). In the current funding cycle, we identified an adverse, long-range consequence of localized ischemia in the sickle milieu:. SCO transforms and disseminates a localized, regional, and otherwise self-remitting ischemic insult into a systemic, nflammatory process attended by vaso-occlusion in distant and vital organs, and ultimately, increased mortality. Tissue ischemia is thus not only a consequence of vaso-occlusive disease but is also a contributor to vaso-occlusion, inflammation, and other pathogenetic pathways in SCO. As in any diseased tissue, adaptive and maladaptive processes are entrained, and in this regard, we hypothesize that in SCO in the unstressed state and in the stressed, postischemic state, a triad of linked responses occurs, and consists of induction of heme oxygenase-1 (HO-1) and p21 as adaptive, protective responses, and induction of monocyte chemoattractant protein-1 (MCP-1) as a maladaptive, injurious process. This theme will be pursued in 4 specific aims: Aim I: Hypothesis: The sickle milieu transforms and disseminates a transient episode of localized ischemia into a systemic, long-range, inflammatory process with widespread vaso- occlusion and dysfunction of distant vital organs. Examination: Alterations in vital organs and tissues, and relevant systemic indices will be analyzed in sickle mice in the unstressed state and following regional ischemia. Aim II: Hypothesis: Induction of HO-1 is an adaptive, protective response in SCO in the unstressed state and following regional ischemia. Examination: Deficiency of HO-1. in the endothelium and kidney using a Cre/lox approach will exacerbate injury in these sites in sickle mice in the unstressed state and following regional ischemia. Aim III: Hypothesis: Induction of MCP-1 (a HO-suppressible gene) is a maladaptive, injurious response in SCO in the unstressed state and following regional ischemia. Examination: Approaches that interrupt either the expression of MCP-1 gene or the efficacy of the MCP-1 protein will decrease tissue injury in sickle mice in the unstressed state and following regional ischemia. Aim IV: Hypothesis: Induction of p21 (an HO-inducible protein) is an adaptive, protective response in SCO in the unstressed state and following regional ischemia. Examination: Deficiency of p21, as modeled by p21 -/- mutant mice, will exacerbate tissue injury in sickle mice in the unstressed state and following regional ischemia. LAY SUMMARY: Decreased blood supply to tissues contributes to organ and tissue damage in sickle cell disease. This application proposes to study how this occurs, and the genes that are induced, specifically, those such as MCP-1 that contribute to injury, and those such as HO-1 and p21 that protect against such injury. Such information may assist in devising new treatments for sickle cell disease.

组织缺血是血管闭塞性镰状细胞病(SCO)的结果。在当前的筹资周期中， 我们确定了镰刀环境中局部缺血的不利的长期后果：上海合作组织转型 并将局部的、区域性的和其他自我缓解的缺血性侮辱传播到系统性的、 炎症过程伴随着远处和重要器官的血管闭塞，并最终增加 死亡率。因此，组织缺血不仅是血管闭塞性疾病的后果，而且也是一个因素 与血管闭塞、炎症和其他致病途径有关。就像在任何病变组织中一样， 适应性和非适应性进程是附带的，在这方面，我们假设上海合作组织在 在非应激状态和应激、缺血后状态下，三联体反应发生，并包括 诱导血红素加氧酶-1(HO-1)和p21作为适应性、保护性反应和诱导 单核细胞趋化蛋白-1(MCP-1)是一种不适应、损伤的过程。这个主题将是 追求四个具体目标：目标一：假设：镰刀环境转变并传播一种瞬变 局灶性缺血转变为全身性、长程、炎症过程，并伴有广泛的血管- 远处重要器官的闭塞和功能障碍。检查：重要器官和组织的改变，以及 分析镰刀鼠在非应激状态和以下区域的相关系统指标 缺血症。目的II：假设：HO-1的诱导是一种适应性的保护性反应，在 无应激状态和区域缺血后。检查：HO-1缺乏症。在内皮细胞和 使用CRE/LOX方法的肾脏将在非应激状态下加重镰刀鼠这些部位的损伤 以及在局部缺血后。目的III：假设：MCP-1(一种HO抑制基因)的诱导是一种 上海合作组织在非应激状态和区域缺血后的不适应、损伤性反应。 检查：干扰MCP-1基因表达或MCP-1疗效的方法 蛋白质将减少镰刀鼠在非应激状态和局部缺血后的组织损伤。目标 IV：假设：p21(一种HO诱导的蛋白)的诱导是一种适应性的保护性反应，在 无应激状态和区域缺血后。检查：p21缺乏症，如p21-/- 突变小鼠，在非应激状态和以下区域，将加剧镰刀鼠的组织损伤 缺血症。 综述：组织供血减少导致镰状细胞的器官和组织损伤 疾病。这项应用旨在研究这种情况是如何发生的，以及被诱导的基因，特别是， 如MCP-1等导致损伤的基因，以及如HO-1和p21等保护细胞免受伤害的基因 受伤。这些信息可能有助于设计治疗镰状细胞病的新方法。