Immune mechanisms in collapsing glomerulopathy

塌陷性肾小球病的免疫机制

• 批准号: 6841308
• 负责人: PETER JACOB NELSON
• 金额: $ 13.26万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841308
• 关键词: biological signal transduction; cell differentiation; cell migration; cellular immunity; cellular polarity; clinical research; cyclin dependent kinase; disease /disorder model; enzyme induction /repression; flavopiridol; genetically modified animals; glomerulosclerosis; helper T lymphocyte; immune response; immunocytochemistry; immunomodulators; kidney disorder chemotherapy; kinase inhibitor; laboratory mouse; leukocyte activation /transformation; lithium; nonhuman therapy evaluation; pathologic process; purines; serine threonine protein kinase

DESCRIPTION (provided by applicant): Collapsing glomerulopathy, a clinically aggressive and therapeutically resistant variant of focal segmental glomerulosclerosis, has become a major cause of end-stage renal disease within the last two decades. Collapsing glomerulopathy is associated with disorders that induce strong T helper type 1 (Th1) immune responses, suggesting not only that Th1 effectors play an important role in the pathogenesis of collapsing glomerulopathy, but also that immunomodulation in collapsing glomerulopathy should be investigated. We recently determined in pre-clinical studies that small molecule cyclin-dependent kinase (CDK)/glycogen synthesis kinase-3( (GSK-3() inhibitors may be very effective therapy for collapsing glomerulopathy, however, their immunomodulatory properties, particularly via GSK-3(, a key signaling molecule in CD4+ T lymphocyte activation, are poorly understood. In this study, we propose the following specific aims: 1) to determine in CD4+ mouse lymphocytes whether GSK-3( deletion by inhibitory RNA, GSK-3( inhibition by lithium, or CDK/GSK-3( inhibition by flavopiridol or roscovitine, suppress specific induction or effector responses of Th1-polarizing or Th2-polarizing lymphocytes in vitro; 2) to determine in mice whether flavopiridol or roscovitine suppress specific effector responses of committed Th1 or Th2 splenocytes at efficacious doses for collapsing glomerulopathy in vivo; 3) to determine whether systemic Th1 or Th2 immune deviation retards or accelerates the development of renal disease in the Tg26 HIV-1 transgenic mouse model of collapsing glomerulopathy; and 4) to determine in kidney biopsies from the NIH/NYU Podocyte Disease Registry whether CD4+ Th1 effectors rather than CD4+ Th2 effectors traffic to kidneys with collapsing glomerulopathy when compared to other variants of focal segmental glomerulosclerosis. These studies should elucidate important cell-mediated immune mechanisms in the pathogenesis of collapsing glomerulopathy and delineate the therapeutic specificity of small molecule CDK/GSK-3( inhibitors in the immune deviation of collapsing glomerulopathy-associated disorders

描述（由申请人提供）： 在过去的二十年中，肿胀的肾小球病是一种临床上具有侵略性和治疗性抗性变体，已成为终末期肾脏疾病的主要原因。崩溃的肾小球病与诱导强型T辅助辅助1（Th1）免疫反应有关，不仅表明TH1效应子在崩溃的肾小球病的发病机理中起着重要作用，还应研究张胶质性肾小球肿瘤的免疫调节。 We recently determined in pre-clinical studies that small molecule cyclin-dependent kinase (CDK)/glycogen synthesis kinase-3( (GSK-3() inhibitors may be very effective therapy for collapsing glomerulopathy, however, their immunomodulatory properties, particularly via GSK-3(, a key signaling molecule in CD4+ T lymphocyte activation, are poorly在这项研究中，我们提出以下特定目的：1）在CD4+小鼠淋巴细胞中确定GSK-3（抑制性RNA删除，GSK-3的删除）在体外的淋巴细胞； 2）在小鼠中抑制了在有效剂量的Th1或Th2脾脏的特定效应子反应中在NIH/NIH/NIH的Podocyte疾病注册表中确定CD4+ TH1效应子，而不是CD4+ TH2与肿胀的肾脏疾病相比，与其他局部性肿瘤的术语相比，肾小球病和描述小分子CDK/GSK-3的治疗特异性（抑制肾小球相关疾病的免疫偏差中的抑制剂