Identification of the neuroinflammatory signature for CTE using single nucleus RNA sequencing

使用单核 RNA 测序鉴定 CTE 的神经炎症特征

• 批准号: 10165503
• 负责人: Jonathan D Cherry
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10165503
• 关键词: Advisory Committees; American; Amyloid beta-Protein; Area; Astrocytes; Autopsy; Behavioral; Bioinformatics; Biological Markers; Boston; Boxing; Brain; Brain Concussion; Brain Diseases; Brain region; Cell Nucleus; Cells; Clinical; Cognitive; Collaborations; Color; Consensus; Craniocerebral Trauma; Data; Deposition; Development; Diagnosis; Disease; Dissection; Endothelial Cells; Environment; Exposure to; Fluorescent in Situ Hybridization; Foundations; Freedom; Freezing; Genes; Genomics; Goals; Heterogeneity; Hippocampus (Brain); Hockey; Hospitals; Human; Human Resources; Immune; Immunohistochemistry; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Jamaica; Knowledge; Laboratory Research; Lesion; Life; Location; Manufactured football; Measures; Memory; Mentors; Methods; Microglia; Military Personnel; Motor; Nerve Degeneration; Neuroanatomy; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Oligodendroglia; Pathogenesis; Pathologic; Pathology; Patients; Phenotype; Play; Population; Process; Proteins; RNA; Recording of previous events; Research; Research Personnel; Resolution; Resources; Risk; Risk Factors; Role; Senior Scientist; Severities; Severity of illness; Shapes; Single Nucleotide Polymorphism; Small Nuclear RNA; Soldier; Stains; Time; Tissues; Training; United States Department of Veterans Affairs; Universities; Veterans; Work; behavioral impairment; brain cell; brain tissue; career; cell type; chronic traumatic encephalopathy; cohort; contact sports; design; differential expression; effective therapy; experience; frontal lobe; hyperphosphorylated tau; immunoregulation; injured; interest; meetings; mild traumatic brain injury; military service; military veteran; neurodegenerative phenotype; neuroinflammation; novel diagnostics; novel marker; novel therapeutics; operation; protein TDP-43; single-cell RNA sequencing; tau aggregation; therapeutically effective; therapy design; transcriptome sequencing

Candidate: The long-term career goal of Dr. Jonathan Cherry is to become an independent VA investigator and establish a research laboratory focused on head trauma and neurodegenerative diseases. Dr. Cherry is primarily interested in how repetitive head trauma received during military service or contact sports contributes toward the development and progression of the neurodegenerative disease chronic traumatic encephalopathy (CTE). During the proposed CDA2, Dr. Cherry will build off his graduate and postdoctoral experience studying neuroinflammation and inflammatory cells, and expand his knowledge of [bioinformatics, single cell RNA- sequencing], human neuroanatomy and clinical disease presentation to accomplish the proposed aims. In addition to formal course work and regular meetings with Dr. Ann McKee (Mentor) and his advisory committee, Dr. Cherry will receive weekly hands-on training in brain dissection. The support provided by the proposed CDA2 will be instrumental in shaping Dr. Cherry into a successful VA investigator, and result in critical and timely knowledge regarding CTE in Veterans. Environment: The Veterans Affairs – Boston University – Concussion Legacy Foundation (VA-BU-CLF) brain bank at VA Boston contains the world’s largest neuropathologically diagnosed cohort of CTE cases and represents the forefront of CTE research. Personnel and senior scientists at the Jamaica Plain VA hospital (VA Boston) and the Boston University Center for the Study of Traumatic Encephalopathy (BU CSTE) are the world’s leading experts in CTE and neurodegeneration. The facilities and personnel provide the ideal environment to perform the training and research described in this proposal. Dr. McKee is an experienced mentor, having trained over 30 researchers of all levels that have had subsequent successful careers. The many centers affiliated with VA Boston and the BU CSTE will also allow for multiple collaborations. Research: Mild traumatic brain injury (mTBI) has been called the “signature injury” of Operation Iraqi Freedom/Operation Enduring Freedom. Furthermore, many soldiers will receive multiple mTBIs. Repetitive head trauma is the single greatest risk factor for developing CTE, a neurodegenerative disease characterized by progressive memory and behavior impairments. Currently, CTE can only be diagnosed post-mortem; thus, the need to understand what factors drive pathology are critical to finding novel biomarkers to diagnose CTE and create effective therapeutics for living patients. Neuroinflammation has recently been implicated in CTE pathologic progression; however, the mechanisms are still unclear. The work proposed in this study aims to understand how neuroinflammation potentially leads to CTE as a consequence of repetitive head trauma. First, [Dr. Cherry will identify all the inflammatory or neurodegenerative cell populations that emerge after repetitive mTBI (rmTBI) using single nucleus RNA sequencing (snRNA-seq). Dr. Cherry will compare the neuroinflammatory cell populations using tissue from individuals with no history of rmTBI and neurodegenerative disease, individuals with history of rmTBI but no neurodegenerative disease, and individuals with a history of rmTBI and CTE stage I or II (i.e. mild CTE). This analysis will identify individual populations of cells and investigate important mechanistic cellular populations that emerge after head trauma and during early CTE. This will be the first study to perform snRNA-seq using human brains with a history of rmTBI. Finally, Dr. Cherry will comprehensively analyze the observed neurodegenerative subpopulations using up to 9 color multiplex staining to visualize the regional location of each population. He will explore if the neurodegenerative subpopulations have interactions with neuropathologic features such as hyperphosphorylated tau, Aβ, or TDP-43.] Overall, results generated from this study are necessary to progress the fundamental understanding of mechanisms behind neuroinflammation after head trauma, identify novel biomarkers to detect CTE, and design therapies to treat disease in living subjects.

候选人：乔纳森·樱桃博士的长期职业目标是成为独立的VA调查员和 建立专注于头部创伤和神经退行性疾病的研究实验室。樱桃博士是主要的 对在服兵役或接触体育期间重复的头部创伤感兴趣 神经退行性疾病的发育和进展慢性创伤性脑病（CTE）。 在拟议的CDA2期间，Cherry博士将建立他的研究生和博士后经验研究 神经炎症和炎症细胞，并扩展他对[生物信息学，单细胞RNA- 测序]，人类神经解剖学和临床疾病表现，以实现拟议的目的。 除了与Ann McKee博士（导师）及其咨询委员会的正式课程工作和定期会议外 Cherry博士将接受每周的大脑解剖培训。拟议的CDA2提供的支持 将有助于将Cherry博士塑造成成功的VA调查员，并导致临时和及时 关于退伍军人中CTE的知识。 环境：退伍军人事务 - 波士顿大学 - 脑震荡遗产基金会（VA-BU-CLF）大脑 波士顿弗吉尼亚州的银行包含世界上最大的神经性诊断的CTE案件和 代表CTE研究的最前沿。牙买加平原医院的人员和高级科学家（VA 波士顿）和波士顿大学创伤性脑病研究中心（BU CSTE）是世界的 CTE和神经退行性的领先专家。设施和人员为 执行本提案中描述的培训和研究。麦基博士是一位经验丰富的精神，经过训练 超过30位随后成功职业的研究人员。许多中心有 VA波士顿和BU CSTE也将允许多次合作。 研究：轻度创伤性脑损伤（MTBI）被称为伊拉克手术的“签名损伤” 自由/操作持久自由。此外，许多士兵将收到多个mtbis。重复的头 创伤是开发CTE的最大危险因素，这是一种神经退行性疾病，其特征是 进行性记忆和行为障碍。目前，CTE只能被诊断出验证后；因此， 需要了解哪些因素驱动病理学对于寻找新型的生物标志物来诊断CTE和 为活着的患者创建有效的疗法。神经炎症最近与CTE有关 病理进展；但是，机制仍然不清楚。本研究提出的工作旨在 了解神经炎症是如何导致重复性头部创伤的结果可能导致CTE的。第一的， [博士樱桃将确定重复后出现的所有炎症或神经退行性细胞群体 使用单核RNA测序（SNRNA-Seq）MTBI（RMTBI）。樱桃博士将比较 神经炎症细胞种群使用没有RMTBI史和神经退行性病史的个体的组织 疾病，有rmtbi史但没有神经退行性疾病的个体 RMTBI和CTE I期或II（即轻度CTE）。该分析将确定单个细胞的种群，并 研究重要的机械细胞种群，这些细胞群体在头部创伤后和CTE早期出现。这 将是第一个使用具有RMTBI史的人类大脑进行SNRNA-SEQ的研究。最后，樱桃博士将 全面分析使用多达9种颜色多重染色的观察到的神经退行性亚群 可视化每个人群的区域位置。他将探讨神经退行性亚群是否 与神经病理学特征有相互作用，例如高磷酸化的TAU，Aβ或TDP-43。] 总体而言，这项研究产生的结果对于进步的基本理解是必要的 头部创伤后神经炎症背后的机制，识别新型生物标志物检测CTE并设计 治疗生命受试者疾病的疗法。