RAE 1 and renal injury

假设：我们最近发现缺血诱导RAE 1的重新表达.对肾 肾小管和肾脏表达NKG 2D，RAE 1的白细胞受体。我们建议 RAE 1的表达允许受损的肾上皮细胞通过NKG 2D被白细胞识别。这种识别激活白细胞并加剧损伤。此外，这种识别可能启动上皮损伤-> RAE 1表达-> NKG 2D白细胞活化->上皮损伤-> RAE 1表达等的“RAE 1-NKG 2D恶性循环”。这可能有助于肾衰竭的进行性。本R21（与肾脏相关的RFA试点和可行性项目，PA-01-127）的总体目标是检验上述假设。虽然我们的建议目前集中在缺血性急性肾功能衰竭，RAE 1的表达也可能发生在其他类型的肾损伤，包括进行性肾功能衰竭的糖尿病和高血压，并有助于在这些疾病中的损伤。 具体目标I：重度肾功能不全后20周内发生进行性肾功能不全 已发表模型中的缺血;在此期间RAE 1和NKG 2D何时表达？ 特定目的II：确定哪些NKG 2D表达白细胞在治疗后导致肾损伤 缺血这样的白细胞可以包括NK细胞、NK T细胞、巨噬细胞、CD 8 T细胞和/或T淋巴细胞。 细胞确定是否可以通过消除特定人群的 这些白细胞使用转基因敲除小鼠和单克隆抗体。 具体目的III：检测体外肾小管细胞上RAE 1表达的调节， in vivo. 本文提出的“RAE 1 -NKG 2D恶性循环”将是对进行性肾损伤的新见解。新的治疗方法可能会阻止这种恶性循环。

Hypothesis: We recently found that ischemia induces the de novo expression of RAE 1. on renal tubules and the renal expression of NKG2D, the leukocyte receptor for RAE 1. We propose that the expression of RAE 1 allows injured renal epithelia to be recognized by leukocytes via NKG2D. This recognition activates the leukocytes and exacerbates injury. In addition, this recognition may initiate a "RAE 1- NKG2D vicious cycle" of epithelial injury -> RAE 1 expression -> NKG2D leukocyte activation -> epithelial injury -> RAE 1 expression, etc. This may contribute to the progressive nature of renal failure. The overall goal of this R21 (RFA pilot and feasibility program related to the kidney, PA-01-127) is to test the above hypothesis. Although our proposal is currently focused on ischemic acute renal failure, expression of RAE 1 may also occur in other types of renal injury, including progressive renal failure in diabetes mellitus and hypertension, and contribute to perpetuating the injury in those diseases. Specific Aim I: Progressive renal insufficiency develops over 20 weeks after severe renal ischemia in published models; when during this period are RAE1 and NKG2D expressed? Specific Aim II: Determine which NKG2D-expressing leukocyte(s) contribute to renal injury after ischemia. Such leukocytes may include NK cells, NK T cells, macrophages, CD8 T cells, and/or T cells. Determine if progressive renal failure is prevented by eliminating specific populations of these leukocytes using transgenic knockout mice, and monoclonal antibodies. Specific Aim III: Examine the regulation of RAE 1 expression on renal tubule cells in vitro and in vivo. The "RAE 1 - NKG2D vicious cycle" proposed here would be a novel insight into progressive renal injury. New therapy might be directed at interdicting this vicious cycle.