Integrative Chemical Biology of Neurodegeneration: Foundation to Novel Therapies

神经退行性变的综合化学生物学：新疗法的基础

• 批准号: 7575625
• 负责人: Daniel Martin Watterson
• 金额: $ 26.43万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575625
• 关键词: Acute; Acute Brain Injuries; Address; Age of Onset; Alzheimer' s Disease; Amyloid beta-Protein; Area; Attenuated; Back; Basic Science; Bioavailable; Biological; Biology; Brain; Brain Injuries; Chemicals; Chronic; Clinical; Clinical Trials; Complement; Complex; Data; Development; Diagnosis; Disease; Disease Progression; Disease susceptibility; Effectiveness; Elements; FDA approved; Foundations; Functional disorder; Future; Hippocampus (Brain); Homeostasis; Human; Individual; Injury; Interleukin-1; Intervention; Investigation; Laboratories; MAPK14 gene; Medical History; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Molecular Target; Monoclonal Antibodies; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurological outcome; Neuronal Injury; Outcome; Peripheral; Predisposition; Principal Investigator; Production; Property; Proteins; Public Health; Recombinant Proteins; Research; Research Personnel; Screening procedure; Staging; Stimulus; Structure; Synapses; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Translating; Translations; Traumatic Brain Injury; Up-Regulation; attenuation; base; behavior change; clinical practice; cytokine; design; drug development; drug discovery; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; in vivo; macromolecule; neglect; nervous system disorder; novel; public health relevance; research study; response; response to injury; restoration; scaffold; small molecule; stressor

DESCRIPTION (provided by applicant): Our overall hypothesis is that restoration of up-regulated CNS proinflammatory cytokine production back towards homeostasis can provide attenuation of neurodegenerative disease progression. Specific to this proposal, we hypothesize that this common mechanism of pathophysiology progression can be targeted for decreasing neurodegeneration related to acute brain injury, injury related to chronic neurodegenerative disease, and the contribution of prior acute brain injury to increased susceptibility to the second injury. The three paradigms address disease progression in complex disorders, with the two-hit model addressing prior medical history contributions to later stage disease. The proposed research will use bioavailable, novel small molecule compounds developed in the principal investigator's laboratory to modulate the brain proinflammatory cytokine surge that contributes to hippocampal synaptic dysfunction. The in vivo brain injuries include an acute impact injury as a surrogate for traumatic brain injury (TBI), an Alzheimer's disease (AD)-relevant injury using toxic forms of human Abeta, and a two-hit injury model of TBI followed by a later AD-relevant injury. The pathophysiology progression endpoints include proinflammatory cytokine levels, and the neurological outcomes endpoints include changes in synaptic marker proteins and hippocampus-dependent behavior changes. The two-hit injury studies are a way to explore initially the neglected question of how a prior brain injury can be a susceptibility factor for age-onset AD and other neurological disorders, and to directly address the potential for developing new therapies that alter short and long term outcomes of brain injury on later neurological disease susceptibility, onset and progression. The ability of bioavailable small molecules that attenuate the up-regulation of brain proinflammatory cytokine levels and modulate the neurological outcomes of brain injuries will provide an integrative chemical biology demonstration of the causal relationships between this common pathophysiology mechanism and brain dysfunctions. Successful completion of the proposed studies will provide a firm foundation for future clinical investigations that seek to translate a large body of public health data into potential therapeutic intervention paradigms, and provide an immediate stimulus to ongoing clinical development of new classes of potential disease-modifying therapeutics. PUBLIC HEALTH RELEVANCE: Successful completion of the proposed studies will provide a foundation for immediate translation of basic science into potential disease-modifying clinical interventions using new classes of therapeutics.

描述(由申请人提供)：我们的总体假设是，上调的中枢神经系统促炎症细胞因子的产生恢复到稳态可以减缓神经退行性疾病的进展。具体到这一建议，我们假设这种共同的病理生理进展机制可以靶向减少与急性脑损伤相关的神经退行性变，与慢性神经退行性疾病相关的损伤，以及先前急性脑损伤对增加第二次损伤的易感性的贡献。这三种模式解决了复杂疾病中的疾病进展，两次打击模式解决了先前的病史对后期疾病的贡献。这项拟议的研究将使用首席研究员实验室开发的可生物利用的新型小分子化合物来调节导致海马区突触功能障碍的脑促炎细胞因子激增。体内脑损伤包括作为创伤性脑损伤(TBI)替代品的急性撞击损伤、使用有毒形式的人类Abeta的阿尔茨海默病(AD)相关损伤，以及两次打击的脑损伤模型，随后是与AD相关的损伤。病理生理进展的终点包括促炎细胞因子水平，神经结果终点包括突触标志物蛋白的变化和海马区依赖的行为变化。两次打击的损伤研究是一种方法，旨在初步探索被忽视的问题，即先前的脑损伤如何成为老年性AD和其他神经疾病的易感因素，并直接解决开发新疗法的可能性，这些新疗法可以改变脑损伤对以后神经疾病的易感性、发病和进展的短期和长期结果。生物可利用的小分子能够减弱脑前炎症细胞因子水平的上调并调节脑损伤的神经结局，这将为这一常见的病理生理机制与脑功能障碍之间的因果关系提供综合的化学生物学证据。拟议研究的成功完成将为未来的临床研究奠定坚实的基础，这些研究试图将大量公共卫生数据转化为潜在的治疗干预范例，并为正在进行的潜在疾病修改疗法的临床开发提供直接刺激。公共卫生相关性：拟议研究的成功完成将为立即利用新的治疗方法将基础科学转化为潜在的改变疾病的临床干预措施奠定基础。