Immune mechanisms in collapsing glomerulopathy

塌陷性肾小球病的免疫机制

• 批准号: 7084636
• 负责人: PETER JACOB NELSON
• 金额: $ 13.36万
• 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/7084636
• 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）： 塌陷性肾小球病是局灶性节段性肾小球硬化症的一种具有临床侵袭性和治疗耐药性的变体，在过去二十年中已成为终末期肾病的主要原因。塌陷性肾小球病与诱发强烈辅助性 T 1 型 (Th1) 免疫反应的疾病相关，表明 Th1 效应子不仅在塌陷性肾小球病的发病机制中发挥重要作用，而且还应研究塌陷性肾小球病中的免疫调节。我们最近在临床前研究中确定，小分子细胞周期蛋白依赖性激酶 (CDK)/糖原合成激酶 3((GSK-3()) 抑制剂可能是治疗塌陷性肾小球病非常有效的疗法，然而，它们的免疫调节特性，特别是通过 GSK -3(，CD4+ T 淋巴细胞激活中的关键信号分子，人们对其知之甚少。在本研究中，我们提出以下具体目标：1) 确定 CD4+ 小鼠淋巴细胞中是否存在GSK-3（通过抑制性 RNA 缺失、GSK-3（通过锂抑制）或 CDK/GSK-3（通过黄酮吡醇或 roscovitine 抑制，在体外抑制 Th1 极化或 Th2 极化淋巴细胞的特异性诱导或效应反应；2）确定小鼠中黄酮哌啶醇或罗可维生素丁是否在有效剂量下抑制已定型 Th1 或 Th2 脾细胞的特异性效应反应以导致塌陷体内肾小球病；3) 确定在塌陷性肾小球病的 Tg26 HIV-1 转基因小鼠模型中，系统性 Th1 或 Th2 免疫偏差是否会延缓或加速肾病的发展； 4) 通过 NIH/NYU 足细胞疾病登记处的肾活检确定与局灶节段性肾小球硬化症的其他变体相比，CD4+ Th1 效应子而非 CD4+ Th2 效应子是否流入塌陷性肾小球病的肾脏。这些研究应阐明塌陷性肾小球病发病机制中重要的细胞介导的免疫机制，并阐明小分子 CDK/GSK-3（塌陷性肾小球病相关疾病免疫偏差抑制剂）的治疗特异性。