Mentored Patient-Oriented Research Career Development Aw

指导以患者为中心的研究职业发展Aw

• 批准号: 6529946
• 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
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6529946
• 关键词: I kappa B beta; biological signal transduction; career; child (0-11); chronic renal failure; clinical research; gene expression; glucocorticoids; hormone sensitivity /resistance; hormone therapy; human subject; immune tolerance /unresponsiveness; kidney transplantation; nephrotic syndrome; nuclear factor kappa beta; pathologic process; pediatric pharmacology; phenotype; polymerase chain reaction; postoperative complications; prednisone; relapse /recurrence; steroids; transplantation immunology; tumor necrosis factor alpha

(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.

（改编自申请人的摘要）：候选人之前的经历 实验室的经验使他了解 肾脏疾病和移植中的免疫过程。 这个提议 在博士的指导下。 William E. Hannon 和 Terry B. Strom 设计 促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 办公室将教育他并使他发展成为一名独立的临床医生 研究者。 SRNS 的类固醇抵抗性质值得研究其背后的因素 类固醇抵抗。 类固醇抑制炎症和其他核因子 通过诱导 IkB α 表达来实现 kappa B (NF-kB) 依赖性过程 (IkBa)，抑制 NF-kB 的激活。 激活 NF-kB 的刺激 包括 T 淋巴细胞共刺激途径（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 NF-kB:IkBa 表达增加 移植后复发性 SRN​​S 和急性同种异体移植排斥的比率；和 3) 循环白细胞中的 NF-kB 表达可预测体内 肾和移植物内 NF-kB 表达。 这个假设的中心假设 建议认为 SRNS 中的类固醇抵抗是持续性的表现 循环刺激继发 NF-kB 激活。 假设 SRNS 是一种导致肾脏特异性疾病的全身性疾病 支持：1) 移植后 SRNS 立即复发； 2) SRNS 中引起蛋白尿的循环因子的证据 肾小球脉管系统的构象变化。 目标是 定义 NF-kB 的扰动、细胞来源和循环触发因素 SRNS 中的表达。 本提案的具体目标是： 1) 确定 SRNS 中 NF-kB 亚基的表达量； 2）确定 SRNS 中 NF-kB 表达受到干扰的特定细胞表型； 3) 测量循环中 TNFa 作为 NF-kB 激活的潜在触发因素 SRNS； 4) 测量作为 NF-kB 潜在触发因素的共刺激通路 在 SRNS 中。 这项研究计划的独特之处在于它涉及详细的 分析可能导致肾损伤的循环免疫因素 特定疾病。 这些研究可以为我们提供见解和指导。 开发类固醇抗性标记物以及新疗法 SRNS。