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

顺式脯氨酸在创伤性脑损伤和血管性痴呆的早期发展和治疗中定向蛋白质毒性

• 批准号: 10689684
• 负责人: Chenxi Qiu
• 金额: $ 10.99万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689684
• 关键词: Advisory Committees; Affect; Age; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; American; Amyloid beta-Protein; Attenuated; Automobile Driving; Behavior; Behavioral; Bilateral; Biology; Blood Vessels; Brain; Brain Injuries; Carotid Stenosis; Cell Culture Techniques; Cells; Cessation of life; Chronic; Clinic; Clinical; Cognitive; Data; Dementia; Dependovirus; Development; Disease; Disease Progression; Early Intervention; Environment; Equilibrium; Genetic; Genetic Screening; Genetic Transcription; Goals; Grant; Human; Hypoxia; Impaired cognition; In Vitro; Individual; Knock-out; Knockout Mice; Lead; MAPK10 gene; Mentors; Modeling; Molecular; Molecular Conformation; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Hypoxia; Neurons; Nuclear; Pathogenicity; Pathologic; Pathology; Patients; Phase; Phosphorylation; Phosphotransferases; Proline; Protein Kinase; Proteome; Publishing; Research; Resistance; Risk Taking; Role; Stress; Stroke; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Training; Transcription Repressor; Traumatic Brain Injury; United States National Institutes of Health; Vascular Dementia; age related neurodegeneration; aging brain; career; cell type; cerebral hypoperfusion; chronic traumatic encephalopathy; conditional knockout; excitatory neuron; excitotoxicity; gene repression; healthy aging; induced pluripotent stem cell; inhibitor; insight; medical schools; minimally invasive; mouse model; multidisciplinary; neuropathology; neuroprotection; overexpression; pre-clinical; preservation; prevent; programs; proteotoxicity; response; single nucleus RNA-sequencing; spatiotemporal; tau Proteins; tau conformation; tau mutation; tau-1; transcription factor; transcriptome; transcriptomics

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.

项目摘要 早期干预对于抑制阿尔茨海默病（AD）和相关神经退行性疾病的进展至关重要。 紊乱顺式磷酸化Thr 231-Pro tau（cis P-tau）被认为是早期和致病性tau蛋白 构象驱动AD、创伤性脑损伤（TBI）和血管性痴呆（VaD）中的神经变性。在这 建议，我将探讨TBI和脑灌注不足如何导致顺式P-tau诱导，以及神经元如何 潜在地拮抗顺式P-tau和其它形式的早期tau病理学， 兴奋性神经元的反应。通过无偏遗传筛选，JNK 3已成为第一个激酶， 直接磷酸化cis tau并识别不寻常的顺式构象中的脯氨酸。此外，单- 细胞转录谱和大量的初步数据一致支持REST驱动的神经元 在脑损伤后的前驱期，这种反应可能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JNK 3诱导顺式P-tau蛋白和神经变性的程度 在TBI/VaD小鼠和患者（Aim 1，K99期）中，以确定早期诱导的REST是否抑制顺式P-tau和/或 在培养物、TBI/VaD小鼠和患者（Aim 2，K99+ R 00期）中赋予神经保护作用，并评估 TBI/VaD慢性期早期JNK 3抑制和REST表达拯救的治疗潜力 小鼠（Aim 3，R 00期）。在辅导K99阶段，研究目标是确定JNK 3的程度， REST在接受训练的同时调节顺式P-tau蛋白。在R 00阶段，研究目标是无偏地 并严格评估通过干扰JNK 3和REST调节顺式P-tau蛋白的治疗潜力， TBI和VaD小鼠模型的不同阶段。短期职业目标是接受多学科培训 从该领域的专家，完成拟议的研究，申请第一个NIH R 01补助金，并建立 一项研究计划，研究与顺式P-tau的诱导和调节相关的机制，这是一个强大的，早期的 以及脑外伤、血管性痴呆和AD中神经变性的药物驱动因素。长期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发病的早期机制。培训导向 扬克纳实验室，多学科咨询委员会团队和高度协作和资源丰富的环境 在哈佛医学院遗传学系提供多样化的技术和专业培训， 符合这个目标。