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

• 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
• 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

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的慢性肾脏疾病的患者中的一个不变发现，它是长期预后和进展以结束阶段肾衰竭的少数可修改风险因素之一。无论原始病因如何，肾小球蛋白尿的病理学基础是足功能障碍或损伤。有证据表明，多任务激酶糖原合酶激酶（GSK）3在介导多种固体器官中介导急性和慢性损伤（包括肾脏）中起着重要作用。 GSK3的抑制可以防止肾脏损伤，并代表了一种新型的肾脏保护策略。此处提出的研究将破译GSK3在足细胞功能障碍中的推定作用，并检验了新的假设，即GSK3的阻断可保护足细胞免受损伤，改善蛋白尿和肾小球硬化的缓慢进展。 AIM 1将检查GSK3在阿霉素诱导的足细胞中培养的足细胞中的作用。在足细胞中的GSK3活性将通过RNA干扰或非活性或不可抑制的突变体GSK3的异位表达来特异性操纵。 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将确定强力霉素诱导型足细胞特异性GSK3基因敲除对成年小鼠中adriamycin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效应，而GSK3的Podocyte特异性阻断是不可能的。在AIM1中鉴定出的致病机制，GSK3促进足细胞损伤将在敲除小鼠的体内验证。 AIM 3将测试TDZD-8的预防和拯救效应，TDZD-8是GSK3的一种新型的非ATP竞争性小分子抑制剂，对adrimycin诱导的肾病。 TDZD-8的功效将与低剂量锂（一种具有强大GSK3抑制作用的安全有效的药物，已经存在数十年，可以用于临床试验之前的几年，在肾脏特定的GSK3封锁之前可以使用。 TDZD-8或锂对阿霉素诱导的足细胞损伤和相关机制的影响。总的来说，这些研究应允许快速进展到具有GSK3抑制活性的现有药物的临床试验，以改善足细胞损伤，诱导蛋白尿缓解以及人肾小球硬化的缓慢进展。 公共卫生相关性：蛋白尿是大多数类型的慢性肾脏疾病的患者中的一个不变发现，并且是促进肾小球硬化和末期肾衰竭发展的最终常见途径。肾小球蛋白尿的病理基础是足细胞功能障碍和损伤。改善蛋白尿的现有策略，包括糖皮质激素和细胞毒性药物，具有严重的副作用和有限的效用。此处提出的研究将提供有关在调节足细胞损伤调节的新细胞信号分子的全面图片，并研究一种完全新颖的治疗方法，用于衰减基于阻断该分子的蛋白尿。这些研究应允许快速进展到具有阻塞活性的现有药物的临床试验，以改善足细胞损伤，诱导蛋白尿缓解以及人肾小球硬化的缓慢进展。