RAE 1 and renal injury

假设：我们最近发现缺血诱导肾脏RAE 1从头表达 肾小管和RAE-1的白细胞受体NKG2D的表达。 RAE-1的表达使受损的肾上皮细胞能够通过NKG2D被白细胞识别。这种认识激活了白细胞，加重了损伤。此外，这种认识可能会启动上皮损伤--RAE-1表达--NKG2D白细胞激活--上皮损伤--RAE-1表达等“RAE-1-NKG2D恶性循环”。这可能有助于肾功能衰竭的进行性。R21(与肾脏相关的RFA试点和可行性计划，PA-01-127)的总体目标是验证上述假设。虽然我们的建议目前主要集中在缺血性急性肾功能衰竭，但RAE-1的表达也可能发生在其他类型的肾损伤中，包括糖尿病和高血压的进行性肾功能衰竭，并有助于这些疾病的持久损伤。 具体目标一：严重肾功能不全后20周出现进行性肾功能不全 在已发表的模型中，RAE1和NKG2D在什么时候表达？ 特定目的II：确定哪些表达NKG2D的白细胞(S)在急性肾损伤中起作用 缺血症。这种白细胞可以包括NK细胞、NK T细胞、巨噬细胞、CD8 T细胞和/或T细胞 细胞。确定是否通过消除特定人群来预防进行性肾功能衰竭 这些白细胞用转基因基因敲除的小鼠和单抗。 特异性目的III：检测体外培养的肾小管上皮细胞RAE-1表达的调节 在活体内。 这里提出的“RAE-NKG2D恶性循环”将是对进行性肾损伤的一种新的见解。新的治疗方法可能旨在阻断这一恶性循环。

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.