Integrative Chemical Biology of Neurodegeneration: Foundation to Novel Therapies

描述（由申请人提供）：我们的总体假设是，将上调的中枢神经系统促炎细胞因子生产恢复到稳态可以减弱神经退行性疾病的进展。针对这一建议，我们假设这一共同的病理生理进展机制可以靶向减少急性脑损伤相关的神经退行性变，慢性神经退行性疾病相关的损伤，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，其中两种模式解决了先前的病史对后期疾病的贡献。拟议的研究将使用由首席研究员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。体内脑损伤包括急性撞击损伤作为创伤性脑损伤（TBI）的替代品，阿尔茨海默病（AD）相关损伤使用有毒形式的人类Abeta，以及TBI的两次撞击损伤模型，随后发生AD相关损伤。病理生理进展终点包括促炎细胞因子水平，神经学终点包括突触标记蛋白的变化和海马依赖行为的改变。两次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性AD和其他神经系统疾病的易感性因素，并直接解决开发新疗法的潜力，这些新疗法可以改变脑损伤对后期神经系统疾病易感性、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促炎细胞因子水平的上调并调节脑损伤的神经系统结果，这将为这一常见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论证。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，这些研究将寻求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改善疗法的临床开发提供直接刺激。公共卫生相关性：成功完成拟议的研究将为使用新型治疗方法将基础科学立即转化为潜在的改善疾病的临床干预提供基础。

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.