The Role of C3a and C5a in BEA Induced Nephritis

描述(由申请人提供)：在他的儿科肾病临床研究员和他的免疫学博士后培训期间，他的兴趣一直集中在补体和宿主免疫反应的关系上。这项建议对候选人来说是在一个良好的研究环境中工作的绝佳机会，这将极大地有助于候选人对补体生物学以及肾脏损伤的免疫学方面的知识。这一建议基于两个不同但又相互关联的发现：第一，过敏性毒素受体C3a和C5a在近端肾小管上皮细胞中高度表达，第二，C3a和C5a具有减弱CD4+Th1 T细胞反应的能力。基于C3a和C5a直接作用于近端肾小管上皮细胞和适应性免疫反应促进肾损伤的假设，我们建议确定C3a和C5a在小鼠2-溴乙胺(BEA)肾炎模型中的作用。首先，我们将研究C3a和C5a受体在原代小鼠近端肾小管上皮细胞中的表达和功能。其次，在C3a和C5a受体缺陷小鼠中，将定义与抗原提呈细胞和T细胞功能相关的免疫反应，以及T细胞依赖的B细胞激活。最后，在BEA诱导的肾炎的急性肾小管坏死期和慢性肾小管间质病期，C3a和C5a受体缺陷小鼠和野生型小鼠之间的功能和组织学差异将被明确。此外，将从肾组织中分离单个核细胞，对其进行表型分析，并在蛋白质和信使核糖核酸水平上鉴定细胞因子的产生模式。候选人和赞助商的兴趣在于了解过敏性毒素在免疫介导的发病机制中的作用。该提案的努力将直接适用于人类疾病。在这一奖项完成后，候选人将准备继续在肾脏免疫病理领域作为一名富有成效的独立研究员

DESCRIPTION (provided by applicant):Throughout his clinical fellowship in pediatric nephrology and his postdoctoral training in immunology the candidate's interests have been focused on the relationship of complement and host immune response. This proposal represents an excellent opportunity for the candidate to work in a well regarded research environment which will contribute immensely to the candidate's knowledge of complement biology as well as immunologic aspects of renal injury. This proposal is based on two distinct, but interrelated findings; first, that the receptors for the anaphylatoxins, C3a and C5a, are highly expressed in proximal tubular epithelium, and second thatC3a and C5a have the capacity to attenuate CD4+ Thl T-cell responses. Based on the hypothesis that C3a and C5a, acting directly on proximal tubular epithelial cells and on the adaptive immune response, promote renal injury, we propose to define the role of C3a and C5a in the murine 2-Bromoethylamine (BEA) nephritis model. Initially, we will characterize both the expression and function of the C3a and C5a receptors in primary murine proximal tubular epithelial cells. Second, immunologic responses with respect to antigen presenting cell and T-cell function, as well as T-cell dependent B-cell activation will be defined in C3a and C5a receptor deficient mice. Lastly, functional and histological differences between C3a and C5a receptor deficient mice and wildtype littermate controls will be defined in both the acute tubular necrosis phase and the chronic tubulointerstitial disease phase of BEA induced nephritis. In addition, mononuclear cells will be isolated from renal tissue, phenotyped, and functionally characterized by patterns of cytokine production both at the protein and mRNA levels. The candidate's and the sponsor's interests are in understanding the role of the anaphylatoxins in immune mediated pathogenesis. The efforts of the proposal will have direct application to human disease. At the completion of this Award, the candidate will be prepared to continue as a highly productive independent investigator in the area of renal immunopathogenesis