Mentored Patient-Oriented Research Career Development Aw

(改编自申请人的摘要)：候选人以前的 实验室的经验使他对 肾脏疾病和移植中的免疫学过程。这项建议 在威廉·E·汉农和特里·B·斯特罗姆博士的指导下， 推进申请人在免疫学研究应用方面的培训 SRNS。此外，临床研究核心计划内的环境 办公室将教育并使他能够发展成为一名独立的诊所 调查员。 SRNS的类固醇抵抗性质需要研究其背后的因素 类固醇抗药性。类固醇抑制炎症和其他核因子 Kappa B(核因子-kB)诱导IKBα表达的依赖过程 (IkBA)，抑制核因子-kB的激活。激活核因子-kB的刺激 包括T淋巴细胞共刺激通路(CD28/B7、CD40/CD154)，以及 肿瘤坏死因子α(TNFa)。申请人已证明：1) SRNS患者肾内IkBA表达减弱 对类固醇治疗的反应；2)移植物内核因子-kB的表达增加：Ikba 移植后复发SRNS和移植急性排斥反应的比率；以及 3)循环白细胞中核因子-kB的表达可预测血管内皮细胞损伤。 肾组织和移植肾内核因子-kB的表达。这一点的中心假设是 认为SRNS中的类固醇抵抗是一种持续性的 核因子-kB的激活继发于循环刺激。假设 SRNS是一种导致肾脏特有疾病的全身性疾病 支持：1)移植后SRNS的即刻复发； 2)SRNS中的循环因子可导致蛋白尿和 肾小球血管系统的构象变化。目标是 定义核因子-kB的扰动、细胞来源和循环触发因素 在SRNS中的表达。该提案的具体目的是：1)确定 核因子-kB亚单位在SRNS中的表达；2)确定 在SRNS中表现出特定的细胞表型，表现为NF-kB表达受扰； 3)检测循环中的肿瘤坏死因子α作为核因子-kB激活的潜在触发器。 SRNS；以及4)测量共刺激通路作为核因子-kB的潜在触发因素 在SRNS。这项研究方案是独一无二的，因为它涉及到一个详细的 可能导致肾脏损害的循环免疫因素分析 特定的疾病。这些研究可能会为我们提供洞察和指导 类固醇耐药标记物的研究进展及治疗方法 SRNS。

(Adapted from the applicant's abstract): The candidate's previous experience in the laboratory has provided him with an understanding of immunological processes in renal diseases and transplantation. This proposal under the mentorship of Drs. William E. Hannon and Terry B. Strom is designed to advance applicant's training in the application of immunological studies to SRNS. Moreover, the environment within the Clinical Research Core Program Office will educate and enable him to develop into an independent clinical investigator. The steroid resistant nature of SRNS warrants study of factors that underlie steroid resistance. Steroids suppress inflammatory and other nuclear factor kappa B (NF-kB)-dependent processes by inducing expression of IkB alpha (IkBa), which inhibits activation of NF-kB. Stimuli which activate NF-kB include the T lymphocyte co-stimulatory pathways (CD28/B7, CD40/CD154), and tumor necrosis factor alpha (TNFa). The applicant has shown: 1) that patients with SRNS demonstrate attenuated intra-renal expression of IkBa in response to steroid therapy; 2) increased intra-graft expression of NF-kB:IkBa ratio in post-transplant recurrent SRNS and acute allograft rejection; and 3) that NF-kB expression in circulating leukocytes is predictive of intra- renal and intra-graft NF-kB expression. The central hypothesis of this proposal is that steroid-resistance in SRNS is a manifestation of sustained NF-kB activation secondary to a circulating stimulus. The hypothesis that SRNS is a systemic disorder resulting in a kidney-specific disease is supported by: 1) the immediate recurrence of SRNS following transplantation; and 2) evidence of circulating factors in SRNS that cause proteinuria and conformational changes in the glomerular vasculature. The objectives are to define perturbations, cell sources, and circulating triggers of NF-kB expression in SRNS. The specific aims of this proposal are: 1) to determine the magnitude of expression of NF-kB sub-units in SRNS; 2) to determine the specific cell phenotypes which exhibit perturbed NF-kB expression in SRNS; 3) to measure circulating TNFa as a potential trigger of NF-kB activation in SRNS; and 4) to measure co-stimulatory pathways as potential triggers of NF-kB in SRNS. This research proposal is unique in that it involves a detailed analysis of circulating immunological factors that may result in a kidney specific disease. These studies may provide insight and guidance for the development of markers of steroid resistance as well as novel therapies for SRNS.