Renal Vascular Injury

组织缺血是血管闭塞性镰状细胞病（SCO）的结果。在目前的供资周期中， 我们确定了镰状环境中局部缺血的不利的长期后果。上海合作组织转变 并将局部的、区域性的和其它自我缓解的缺血性损伤扩散到全身， 炎症过程伴随着远端和重要器官的血管闭塞，最终增加 mortality.因此，组织缺血不仅是血管闭塞性疾病的结果， 血管阻塞、炎症等多种致病途径。就像任何病变组织一样， 适应和适应不良的过程中夹带，在这方面，我们假设，在上海合作组织在 在无压力状态和有压力的缺血后状态下，会发生三联反应，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， 单核细胞趋化蛋白-1（MCP-1）作为一种适应不良的有害过程。这个主题将是 追求4个具体目标：目标一：假设：镰刀环境转化和传播一个短暂的 局部缺血发作为全身性、长范围、炎症过程，伴有广泛的血管- 远端重要器官的闭塞和功能障碍。检查：重要器官和组织的变化，以及 将在未应激状态下的镰状小鼠中分析相关的全身指标， 缺血目的II：假设：HO-1的诱导是SCO中的适应性保护反应， 非应激状态和随后的局部缺血。检查：HO-1缺乏。在内皮细胞中， 使用Cre/lox方法的肾脏将加重处于非应激状态的镰状小鼠中这些部位的损伤 和局部缺血后。目的III：假设：MCP-1（HO-抑制基因）的诱导是一个重要因素。 SCO在非应激状态和区域缺血后的适应不良、损伤性反应。 检查：阻断MCP-1基因表达或MCP-1功效的方法 蛋白质将减少镰状小鼠在非应激状态和局部缺血后的组织损伤。目的 IV：假设：p21（HO诱导蛋白）的诱导是SCO中的适应性保护反应， 非应激状态和随后的局部缺血。检查：p21缺陷，以p21 -/-为模型 突变小鼠，将加剧镰状小鼠在无应激状态下的组织损伤， 缺血 概述：镰状细胞病患者组织供血减少导致器官和组织损伤 疾病这项申请提出研究这是如何发生的，以及被诱导的基因，特别是， 那些如MCP-1，有助于损伤，和那些如HO-1和p21，防止这种 损伤这些信息可能有助于设计镰状细胞病的新疗法。

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.