Development of an Agonist of the TGF-beta Signaling Pathway to Treat Alzheimer's

开发 TGF-β 信号通路激动剂来治疗阿尔茨海默病

• 批准号: 8228136
• 负责人: TONY WYSS-CORAY
• 金额: $ 86.18万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228136
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Age; Agonist; Alzheimer' s Disease; Amyloid; Behavioral; Biological Assay; Biological Availability; Bioluminescence; Blood - brain barrier anatomy; Brain; Brain Injuries; Canis familiaris; Cell Culture Techniques; Cell Line; Cells; Characteristics; Chemicals; Chronic; Clinical Trials; Collaborations; Counseling; Cytochrome P450; Development; Dose; Drug Interactions; Drug Kinetics; Eligibility Determination; Evaluation; Failure; Gene Activation; Genes; High Pressure Liquid Chromatography; Hippocampus (Brain); Human; Image; Immune response; Impaired cognition; In Vitro; Injury; Intellectual Property; International; Investigational Drugs; Investigational New Drug Application; Kainic Acid; Knowledge; Lawyers; Lead; Legal patent; Libraries; Licensing; Life; Liver; Materials Testing; Maximum Tolerated Dose; Measures; Metabolic; Modeling; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; No-Observed-Adverse-Effect Level; Oral; Pathogenesis; Pathology; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Principal Investigator; Process; Production; Property; Rattus; Recombinant Transforming Growth Factor; Reporter; Reporter Genes; Reporting; Research Personnel; Route; Safety; Schedule; Screening procedure; Signal Pathway; Signal Transduction; Structure; Structure-Activity Relationship; System; Technology; Testing; Therapeutic; Time; Toxic effect; Toxicogenetics; Toxicokinetics; Toxicology; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Transgenic Organisms; Water; absorption; analog; base; compound 30; conditioned fear; cytokine; design; effective therapy; efficacy testing; excitotoxicity; improved; in vitro Assay; in vivo; in vivo Model; meetings; metabolic abnormality assessment; mouse model; mutant; neuron loss; neuroprotection; neurotoxicity; neurotrophic factor; novel; overexpression; pharmacokinetic characteristic; pre-clinical; preclinical safety; preclinical toxicity; prevent; programs; receptor expression; research study; response; response to injury; scaffold; scale up; small molecule; small molecule libraries; success; tau Proteins

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive cognitive dysfunction. Current knowledge of the processes leading to AD is still limited, and no effective treatments are available. Because neurodegeneration is associated with injury and activation of innate immune responses in the brain, drugs that could mimic the beneficial aspects of this response are potential therapeutic candidates. The cytokine transforming growth factor (TGF)-¿1 is an organizer of the brain's response to injury and has been shown to have neuroprotective effects in models of brain injury and degeneration. Recombinant TGF-¿1 has been used to treat various forms of brain injury in vivo but delivery is not suitable for human use. Studies from our lab have demonstrated that TGF-¿1 can reduce the overall accumulation of A¿, a key factor in AD pathogenesis, in mouse models for AD and in cell culture. Numerous studies have also demonstrated that TGF-¿1 is a potent neurotrophic factor, although high-level chronic TGF-¿1 production can also be detrimental. Recently, we reported that reduced TGF-¿1 expression in vivo or in cultured neurons increases neurodegeneration. Additional studies show that reducing TGF-¿ signaling in neurons of a mouse model for AD increases A¿ accumulation and neurodegeneration and that TGF-¿ receptor expression is reduced in human AD brains. We have identified bioactive small molecule chemical compounds that can activate the TGF-¿ signaling pathway in hippocampal neurons of mice and that pass the blood-brain barrier. With reporter cell lines for the TGF-¿ signaling pathway we screened a diverse small molecule drug library and identified several compounds that are able to activate the reporter system in vitro and in TGF-¿ reporter mice in vivo. The compounds induce specific TGF-¿-responsive genes in cell culture consistent with Smad dependent activation of the TGF-¿ pathway. These chemicals share common properties from which we propose here to derive a lead compound within 5 years. This project includes structure activity relationship analysis of identified active compounds, medicinal chemistry, toxicology and pharmacology in a subcontract with SRI International. Compounds will be tested in neuroprotection and neurotoxicity assays in cell culture and in TGF-¿ reporter mice in vivo. The two most promising compounds will then be tested in an in vivo model of neurodegeneration and in a mouse model for AD. Part of the in vivo analysis on neurodegeneration will be done in collaboration with researchers at UCSD. At the end of our studies we propose to have for the first time a novel neuroprotective and amyloid reducing investigational new drug based on the TGF-¿ signaling pathway for testing in patients with AD.

描述（由适用提供）：阿尔茨海默氏病（AD）是一种神经退行性疾病，会导致进行性认知功能障碍。当前对导致广告的过程的了解仍然有限，并且没有有效的治疗方法。由于神经变性与大脑中先天免疫反应的损伤和激活有关，因此可以模仿该反应的有益方面的药物是潜在的治疗候选者。细胞因子转化生长因子（TGF） - 1是大脑对损伤反应的组织者，已被证明在脑损伤和变性模型中具有神经保护作用。重组TGF-¿1已用于治疗体内各种形式的脑损伤，但递送不适合人类使用。 我们实验室的研究表明，TGF- - 1可以减少A a的总体积累，这是AD和细胞培养的小鼠模型中AD发病机理的关键因素。许多研究还表明，TGF-€1是一种潜在的神经营养因子，尽管还可以确定高级慢性TGF-€1产生。最近，我们报道了体内或培养神经变性中TGF-€1的表达降低。其他研究表明，在小鼠模型的神经元中降低TGF-？用于AD的神经元增加了A的积累和神经变性，并且在人AD大脑中，TGF- - 受体表达降低。 我们已经鉴定出可以激活小鼠海马神经元中TGF- - 信号通路并通过血脑屏障的生物活性小分子化合物。使用TGF-oom信号通路的报告细胞系，我们筛选了潜水员小分子药物库，并鉴定出了几种能够在体外和TGF-€报告中激活记者系统的化合物。这些化合物在细胞培养中诱导特定的TGF-emant响应基因，与TGF- - 途径的SMAD依赖性激活一致。这些化学物质具有共同的特性，我们在此提议在5年内得出铅化合物。该项目包括与SRI International的分包合同中确定的活性化合物，药物化学，毒理学和药理学的结构活动关系分析。化合物将在细胞培养物和TGF-€报告中的神经保护和神经毒性测定中进行测试。然后，将在神经变性的体内模型和AD的鼠标模型中测试这两种最有希望的化合物。关于神经变性的体内分析的一部分将与UCSD的研究人员合作进行。在研究结束时，我们提议首次基于TGF- - 信号传导途径，首次具有新型神经保护作用和淀粉样蛋白减少了研究新药。