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Mentored Patient-Oriented Research Career Development Aw

指导以患者为中心的研究职业发展Aw

基本信息

批准号：
6785500
负责人：
ASHER D SCHACHTER
金额：
$ 12.55万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2006-07-31
项目状态：
已结题

项目摘要

(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.

（摘自申请人摘要）：申请人以前的实验室的经验使他了解了肾脏疾病和移植中的免疫过程。这项建议在William E.汉农和特里B。Strom设计提高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和使他能够发展成为一个独立的临床调查员 SRNS的类固醇耐药性质保证了研究的因素，类固醇抵抗。类固醇抑制炎症和其他核因子通过诱导Ik B α表达的κ B（NF-κ B）依赖性过程（IkBa），其抑制NF-kB的活化。激活NF-kB的刺激包括T淋巴细胞共刺激途径（CD28/B7，CD40/CD154），和肿瘤坏死因子α（TNF α）。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NF-kB：IkBa表达增加移植后复发性SRNS和急性同种异体移植物排斥反应的比率;以及 3)NF-kB在循环白细胞中的表达是预测内- 肾脏和移植物内NF-kB表达。这个问题的核心假设是 SRNS的类固醇耐药是一种持续的 NF-kB激活继发于循环刺激。的假设 SRNS是一种导致肾脏特异性疾病的全身性疾病，支持因素：1）移植后SRNS立即复发; 和2）SRNS中循环因子引起蛋白尿的证据，肾小球血管的构象变化。其目标是定义NF-kB的扰动、细胞来源和循环触发因素在SRNS中表达。本建议的具体目标是：1）确定 SRNS中NF-kB亚单位表达的幅度; 2）确定SRNS中NF-kB亚单位的表达水平。在SRNS中表现出干扰的NF-κ B表达的特定细胞表型; 3)为了测量循环TNF α作为NF-kB激活的潜在触发因素， SRNS;和4）测量作为NF-kB的潜在触发物的共刺激途径在SRNS。这项研究计划的独特之处在于它涉及到一个详细的分析可能导致肾脏疾病的循环免疫因素具体疾病。这些研究可以为研究人员提供洞察力和指导。类固醇耐药标记物的开发以及用于治疗 SRNS。