Therapeutic targeting of GSK3beta: A novel approach for podocyte protection

GSK3beta 的治疗靶向：足细胞保护的新方法

基本信息

批准号：
8158517
负责人：
Rujun Gong
金额：
$ 39.54万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8158517
关键词：
Ablation Acute Adriamycin PFS Adult Adverse effects Albuminuria Animal Model Apoptotic Attenuated Automobile Driving Blood Circulation Blood capillaries CD80 gene Cell Cycle Cell Death Cells Cessation of life Chronic Chronic Kidney Failure Clinical Trials Cytoskeleton Cytotoxic agent Diabetic Nephropathy Disease remission Dose Doxycycline Ectopic Expression End stage renal failure Epithelial Cells Etiology Event FDA approved Foot Process Functional disorder Gap Junctions Gene Targeting Glucocorticoids Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Growth Human Immune Immune System Diseases In Vitro Injury Kidney Kidney Diseases Knock-out Knockout Mice Lithium Mediating Metabolic Mitochondria Modeling Molecular Mus Mutate Natural regeneration Neurons Organ Parietal Pathologic Pathway interactions Patients Permeability Pharmaceutical Preparations Phosphotransferases Physiological Play Preventive Proteins Proteinuria RNA Interference Regulation Renal glomerular disease Risk Factors Role Serine Shapes Signal Transduction Signaling Molecule Solid Staging System Techniques Testing Tetracyclines Threonine Transgenic Mice base capillary glomerulosclerosis hemodynamics improved in vivo inhibitor/antagonist man modifiable risk mutant novel novel strategies novel therapeutic intervention outcome forecast podocyte prevent protective effect small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Proteinuria is an invariable finding in patients with most types of chronic kidney disease and it is one of the few modifiable risk factors for long-term prognosis and progression to end stage renal failure. Regardless of the original etiology, the pathologic basis for glomerular proteinuria is podocyte dysfunction or injury. Evidence suggests that glycogen synthase kinase (GSK) 3, a multi-tasking kinase, plays an important role in mediating acute and chronic injuries in multiple solid organs including the kidney through regulating multiple pathogenic cellular events, such as mitochondria permeability transition (MPT), proinflammatory NFB activation, and cytoskeleton disorganization. Inhibition of GSK3 prevents kidney injury and represents a novel renoprotective strategy. The studies proposed here will decipher the putative role of GSK3 in podocyte dysfunction and test the novel hypothesis that blockade of GSK3 protects podocyte from injury, improves proteinuria and slow progression of glomerulosclerosis. Aim 1 will examine the role of GSK3 in adriamycin induced podocyte injury in cultured podocytes. GSK3 activity in podocytes will be specifically manipulated by RNA interference or ectopic expression of either inactive or non-inhibitable mutant GSK3. The regulatory effect of GSK3 on adriamycin induced podocyte injuries will be assessed, including MPT and the ensuing podocyte death, proinflammatory NFB activation and de novo expression of the costimulatory molecule B7-1, an NFB target gene, as well as podocyte shape changes and the underlying cytockeleton disorganization; Aim 2 will determine the effect of doxycycline inducible podocyte specific GSK3 knockout on adriamycin induced podocytopathy and proteinuria in adult mice. These studies are essential to conclusively elucidate the role of GSK3 in podocyte injury in vivo because selective GSK3 inhibitors may have nonspecific effects and podocyte specific blockade of GSK3 is impossible pharmacologically. Pathogenic mechanisms identified in Aim1 by which GSK3 promotes podocyte injury will be validated in vivo in the knockout mice. Aim 3 will test the preventive and rescue effects of TDZD-8, a novel non-ATP competitive small molecule inhibitor of GSK3 on adriamycin induced nephropathy. The efficacy of TDZD-8 will be compared with low dose lithium, a safe and effective FDA approved drug that possesses potent GSK3 inhibitory actions, already exists for decades and could be used for clinical trials years before kidney specific GSK3 blockade is possible. The effects of TDZD-8 or lithium on adriamycin induced podocyte injury and related mechanisms will be delineated. Collectively, these studies should allow rapid progress to clinical trials of existing drugs with GSK3 inhibitory activities to improve podocyte injury, induce proteinuria remission, and slow progression of glomerulosclerosis in man. PUBLIC HEALTH RELEVANCE: Proteinuria is an invariable finding in patients with most types of chronic kidney disease and is the final common pathway driving progression to glomerulosclerosis and end stage renal failure. The pathologic basis for glomerular proteinuria is podocyte dysfunction and injury. Existing strategies to improve proteinuria, including glucocorticoids and cytotoxic drugs, have severe side effects and limited utility. The studies proposed here will provide a comprehensive picture of a new cellular signaling molecule important in the regulation of podocyte injury and investigate an entirely novel therapeutic approach to attenuate proteinuria based on blocking this molecule. These studies should allow rapid progress to clinical trials of existing drugs with blocking activities to improve podocyte injury, induce proteinuria remission, and slow progression of glomerulosclerosis in man.

描述（由申请人提供）：蛋白尿是大多数类型慢性肾病患者的必然表现，也是长期预后和进展至终末期肾衰竭的少数可改变的危险因素之一。无论最初的病因如何，肾小球蛋白尿的病理基础是足细胞功能障碍或损伤。有证据表明，糖原合酶激酶 (GSK) 3 是一种多任务激酶，通过调节线粒体通透性转变 (MPT) 等多种致病细胞事件，在介导包括肾脏在内的多个实体器官的急性和慢性损伤中发挥重要作用。促炎性 NFB 激活和细胞骨架解体。抑制 GSK3 可预防肾损伤，代表一种新颖的肾脏保护策略。这里提出的研究将破译 GSK3 在足细胞功能障碍中的假定作用，并测试新的假设，即阻断 GSK3 可保护足细胞免受损伤、改善蛋白尿并减缓肾小球硬化的进展。目标 1 将检查 GSK3 在阿霉素诱导的培养足细胞足细胞损伤中的作用。足细胞中的 GSK3 活性将通过 RNA 干扰或失活或不可抑制的突变体 GSK3 的异位表达来专门控制。将评估 GSK3 对阿霉素诱导的足细胞损伤的调节作用，包括 MPT 和随后的足细胞死亡、促炎性 NFB 激活和共刺激分子 B7-1（NFB 靶基因）的从头表达，以及足细胞形状的变化和潜在的细胞骨架紊乱；目标 2 将确定强力霉素诱导的足细胞特异性 GSK3 敲除对成年小鼠阿霉素诱导的足细胞病和蛋白尿的影响。这些研究对于最终阐明 GSK3 在体内足细胞损伤中的作用至关重要，因为选择性 GSK3 抑制剂可能具有非特异性作用，并且足细胞特异性阻断 GSK3 在药理学上是不可能的。 Aim1 中确定的 GSK3 促进足细胞损伤的致病机制将在基因敲除小鼠体内得到验证。目标3将测试TDZD-8（一种新型GSK3非ATP竞争性小分子抑制剂）对阿霉素肾病的预防和挽救作用。 TDZD-8 的功效将与低剂量锂进行比较，低剂量锂是一种安全有效的 FDA 批准的药物，具有有效的 GSK3 抑制作用，已经存在了几十年，并且可以在肾脏特异性 GSK3 阻断成为可能之前几年用于临床试验。将描述TDZD-8或锂对阿霉素诱导的足细胞损伤的影响和相关机制。总的来说，这些研究应该能够使具有 GSK3 抑制活性的现有药物的临床试验取得快速进展，以改善足细胞损伤，诱导蛋白尿缓解，并减缓人类肾小球硬化的进展。公众健康相关性：蛋白尿是大多数类型慢性肾脏病患者的必然表现，也是导致肾小球硬化和终末期肾衰竭进展的最终共同途径。肾小球蛋白尿的病理基础是足细胞功能障碍和损伤。现有的改善蛋白尿的策略，包括糖皮质激素和细胞毒性药物，具有严重的副作用且效用有限。这里提出的研究将提供对足细胞损伤调节中重要的新细胞信号分子的全面了解，并研究基于阻断该分子来减轻蛋白尿的全新治疗方法。这些研究应该能够使现有药物的临床试验取得快速进展，这些药物具有阻断活性，以改善足细胞损伤，诱导蛋白尿缓解，并减缓人类肾小球硬化的进展。