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CNS促炎细胞因子产生恢复到稳态可以提供神经退行性疾病进展的减弱。针对这一提议，我们假设这种常见的病理生理学进展机制可以用于减少与急性脑损伤相关的神经变性、与慢性神经变性疾病相关的损伤以及先前急性脑损伤对第二次损伤易感性增加的贡献。这三种模式解决了复杂疾病的疾病进展，其中两次打击模型解决了先前病史对晚期疾病的贡献。拟议的研究将使用主要研究者实验室开发的生物可利用的新型小分子化合物来调节导致海马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）的替代物的急性撞击损伤、使用毒性形式的人Abeta的阿尔茨海默病（AD）相关损伤以及TBI的两次打击损伤模型，随后是AD相关损伤。病理生理学进展终点包括促炎性细胞因子水平，神经学结局终点包括突触标志物蛋白的变化和视丘依赖性行为变化。两次打击损伤研究是一种探索最初被忽视的问题的方法，即先前的脑损伤如何成为年龄发作性AD和其他神经系统疾病的易感因素，并直接解决开发新疗法的潜力，这些疗法可以改变脑损伤对后期神经系统疾病易感性，发作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促炎细胞因子水平的上调并调节脑损伤的神经学结果，这将为这种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化学生物学证明。拟议研究的成功完成将为未来的临床研究提供坚实的基础，这些临床研究旨在将大量公共卫生数据转化为潜在的治疗干预范例，并为正在进行的新型潜在疾病修饰疗法的临床开发提供直接刺激。公共卫生关系：拟议研究的成功完成将为基础科学立即转化为使用新类别疗法的潜在疾病修饰临床干预提供基础。