Cis proline directed proteotoxicity in the early development and therapy oftraumatic brain injury and vascular dementia

项目摘要 早期干预对抑制阿尔茨海默病(AD)及其相关神经退行性变的进展至关重要 精神错乱。顺式磷酸化Thr231-Pro tau(cis P-tau)被认为是一种早期的致病tau 构象在AD、创伤性脑损伤(TBI)和血管性痴呆(VAD)中驱动神经退行性变。在这 提议，我将探索脑损伤和脑低灌流如何导致顺式P-tau诱导，以及神经元如何 潜在地对抗顺式P-tau和其他形式的早期tau病理通过安装转录 兴奋性神经元的反应。在无偏见的基因筛查中，JNK3已成为第一个激酶 直接磷酸化顺式tau，识别异常顺式构象中的脯氨酸。此外，单人- 细胞转录图谱和大量的初步数据一致支持静息驱动的神经元 在脑损伤后的前驱期，这种反应可能会拮抗这种顺式脯氨酸导向的蛋白毒性。 该提案的目标是确定JNK3诱导顺式P-tau和神经变性的程度 在TBI/VAD小鼠和患者(Aim1，K99期)中，确定早期诱导的REST是否抑制顺式P-tau和/或 在培养、TBI/VAD小鼠和患者(AIM2，K99 R00期)中给予神经保护，并评估 早期抑制JNK3和挽救慢性期静息表达对TBI/VAD的治疗作用 小鼠(Aim3，R00期)。在指导K99阶段，研究目标是确定JNK3和 训练时静息对顺式P-tau的调节作用。在R00阶段，研究目标是不偏不倚 并严格评估通过干扰JNK3调节顺式P-tau的治疗潜力，并在 不同阶段的TBI和VAD小鼠模型。短期的职业目标是接受多学科的培训 来自该领域的专家，以完成拟议的研究，申请第一笔NIH R01拨款，并建立 一项研究计划，研究与顺式P-tau的诱导和调节有关的机制，顺式P-tau是一种强大的早期 以及脑外伤、血管性痴呆和阿尔茨海默病的神经退行性变的可药物驱动因素。长期的职业目标是指导实验室 发现和研究与年龄相关的神经退行性疾病的早期发病机制。以培训为导向 扬克纳实验室、多学科咨询委员会团队以及高度协作和足智多谋的环境 在哈佛医学院遗传学系提供多样化的技术和专业培训 与这个目标保持一致。

Project Summary Early intervention is critical for inhibiting progression of Alzheimer's disease (AD) and related neurodegenerative disorders. Cis phosphorylated Thr231-Pro tau (cis P-tau) has been implicated as an early and pathogenic tau conformation driving neurodegeneration in AD, traumatic brain injury (TBI) and vascular dementia (VaD). In this proposal, I will explore how TBI and cerebral hypoperfusion lead to cis P-tau induction, and how neurons potentially antagonize cis P-tau and other forms of early tau pathology through a mounted transcriptional response in the excitatory neurons. From an unbiased genetic screen, JNK3 has emerged as the first kinase directly phosphorylating cis tau and recognizing the proline in the unusual cis conformation. In addition, single- cell transcriptomic profile and extensive preliminary data consistently support that a REST driven neuronal response may antagonize this cis proline directed proteotoxicity during the prodromal period after brain injuries. The goals of the proposal are to determine the extent to which JNK3 induces cis P-tau and neurodegeneration in TBI/VaD mice and patients (Aim1, K99 phase), to determine if early induced REST inhibits cis P-tau and/or confers neuroprotection in culture, TBI/VaD mice and patients (Aim2, K99+R00 phase) and to evaluate the therapeutic potential of early JNK3 inhibition and rescue of REST expression in the chronic stage in TBI/VaD mice (Aim3, R00 phase). In the mentored K99 phase, the research goal is to determine the extent of JNK3 and REST functions in modulating cis P-tau while receiving training. In R00 phase, the research goal is to unbiasedly and rigorously evaluate the therapeutic potential of modulating cis P-tau by perturbing JNK3 and REST at different stages of TBI and VaD mouse models. The short-term career goal is to receive multidisciplinary training from experts in the field, to complete the proposed studies, to apply for the first NIH R01 grant and to establish a research program to study mechanisms related to the induction and modulation of cis P-tau, a robust, early and druggable driver of neurodegeneration in TBI, VaD and AD. The long-term career goal is to direct a lab to discover and study early mechanisms of onset of age-related neurodegenerative disorders. The training-oriented Yankner lab, multidisciplinary advisory committee team and the highly collaborative and resourceful environment in the Harvard Medical School Department of Genetics offer the diverse technical and professional training in line with this goal.