Development of an Agonist of the TGF-beta Signaling Pthway 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: 7695914
• 负责人: TONY WYSS-CORAY
• 金额: $ 52.64万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7695914
• 关键词: Age; Agonist; Alzheimer' s Disease; Amyloid; Behavioral; Biological Assay; Biological Availability; Bioluminescence; Blood - brain barrier anatomy; Brain; Brain Injuries; Canis familiaris; Cell Line; Cells; Characteristics; Chemicals; Chronic; Clinical Trials; Collaborations; Complement Factor B; Cultured Cells; Cytochrome P450; Development; Dose; Drug Interactions; Drug Kinetics; Eligibility Determination; Evaluation; Failure; Gene Activation; Genes; Hippocampus (Brain); Human; Image; Immune response; Impaired cognition; In Vitro; Injury; International; Investigational Drugs; Investigational New Drug Application; Kainic Acid; Knowledge; Lead; Libraries; Life; Liver; Materials Testing; Maximum Tolerated Dose; Measures; Metabolic; Modeling; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oral; Pathogenesis; Pathology; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Process; Production; Property; Protein Overexpression; Range; Rattus; Recombinant Transforming Growth Factor; Reporter; Reporter Genes; Reporting; Research Personnel; Route; Safety; Schedule; Signal Pathway; Signal Transduction; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Time; Toxic effect; Toxicogenetics; Toxicokinetics; Toxicology; Transformed Cell Line; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Transgenic Organisms; United States Food and Drug Administration; Water; absorption; analog; base; compound 30; conditioned fear; cytokine; design; improved; in vitro Assay; in vivo; in vivo Model; metabolic abnormality assessment; mouse model; mutant; neuron loss; neuroprotection; neurotoxicity; neurotrophic factor; novel; pre-clinical; prevent; receptor expression; research study; response; response to injury; scaffold; scale up; small molecule; small molecule libraries; tau Proteins

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)-Bl 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-B1 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-B1 can reduce the overall accumulation of AB, a key factor in AD pathogenesis, in mouse models for AD and in cell culture. Numerous studies have also demonstrated that TGF-B1 is a potent neurotrophic factor, although high-level chronic TGF-B1 production can also be detrimental. Recently, we reported that reduced TGF-B1 expression in vivo or in cultured neurons increases neurodegeneration. Additional studies show that reducing TGF-B signaling in neurons of a mouse model for AD increases AB accumulation and neurodegeneration and that TGF-B receptor expression is reduced in human AD brains. We have identified bioactive small molecule chemical compounds that can activate the TGF-B signaling pathway in hippocampal neurons of mice and that pass the blood-brain barrier. With reporter cell lines for the TGF-B 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-B reporter mice in vivo. The compounds induce specific TGF-p-responsive genes in cell culture consistent with Smad dependent activation of the TGF-B 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-B 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-B signaling pathway for testing in patients with AD.

阿尔茨海默氏病（AD）是一种神经退行性疾病，导致进行性认知 功能障碍。当前对导致广告过程的过程的了解仍然有限，并且没有有效的治疗方法 可用的。因为神经变性与先天免疫反应的损伤和激活有关 在大脑中，可以模仿该反应的有益方面的药物是潜在的治疗 候选人。细胞因子转化生长因子（TGF）-BL是大脑对 损伤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-B1已用于在体内治疗各种形式的脑损伤，但分娩不合适 用于人类使用。 我们实验室的研究表明，TGF-B1可以减少AB的整体积累，AB的整体积累，这是关键 AD发病机理的因素，AD和细胞培养的小鼠模型中的因素。许多研究也 证明TGF-B1是一种有效的神经营养因子，尽管高级慢性TGF-B1产生 也可能有害。最近，我们报道了体内或培养的TGF-B1表达降低 神经元增加神经退行性。其他研究表明，减少了TGF-B信号的神经元中的TGF-B信号传导 用于AD的小鼠模型增加了AB的积累和神经变性，并且TGF-B受体 人类广告大脑中的表达降低。 我们已经确定了可以激活TGF-B信号的生物活性小分子化合物 小鼠海马神经元的途径，并通过血脑屏障。与记者细胞系一起 TGF-B信号通路我们筛选了一个多样的小分子药物库，并确定了几个 能够在体内在体外和TGF-B报道小鼠中激活记者系统的化合物。这 化合物在与SMAD依赖性一致的细胞培养中诱导特定的TGF-P响应基因 TGF-B途径的激活。这些化学品具有共同特性 在5年内得出铅化合物。该项目包括结构活动关系分析 与SRI分包合同中确定的活性化合物，药物化学，毒理学和药理学 国际的。化合物将在细胞培养和中神经保护和神经毒性测定中进行测试 TGF-B记者在体内。然后，这两种最有希望的化合物将在体内模型中测试 神经变性和AD的鼠标模型。关于神经变性的体内分析的一部分将是 与UCSD的研究人员合作完成。在研究结束时，我们建议第一个 时间是一种基于TGF-B信号的新型神经保护和淀粉样蛋白减少研究的新药 AD患者测试的途径。