权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10664933
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
项目类别：
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/10664933
关键词：
Advisory Committees American Amyloid beta-Protein Area Astrocytes Autopsy Behavioral Bioinformatics Biological Markers Blood Vessels Boston Boxing Brain Brain Concussion Brain region Cells Clinical Cognitive Collaborations Color Consensus Craniocerebral Trauma Data Deposition Development Diagnosis Disease Disease Progression Dissection Endothelial Cells Environment Exposure to Fluorescent in Situ Hybridization Foundations Freedom Freezing Genes Genomics Goals Heterogeneity Hippocampus 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 Postdoctoral Fellow Process Proteins RNA Recording of previous events Recreation Research Research Personnel Resolution Resources Risk Risk Factors Role Senior Scientist Severities Severity of illness Shapes Single Nucleotide Polymorphism Soldier Stains Tissues Training United States Department of Veterans Affairs Universities Veterans Visualization 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 neuropathology novel diagnostics novel marker novel therapeutics operation protein TDP-43 single nucleus RNA-sequencing single-cell RNA sequencing tau aggregation therapeutically effective therapy design

项目摘要

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·切里博士的长期职业目标是成为一名独立的退伍军人管理局调查员

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts.

DOI：
10.1007/s00401-023-02540-w
发表时间：
2023-04
期刊：
Acta neuropathologica
影响因子：
12.7
作者：
通讯作者：

Inflammation and neuronal gene expression changes differ in early versus late chronic traumatic encephalopathy brain.

DOI：
10.1186/s12920-023-01471-5
发表时间：
2023-03-09
期刊：
BMC medical genomics
影响因子：
2.7
作者：
通讯作者：

Associations between near end-of-life flortaucipir PET and postmortem CTE-related tau neuropathology in six former American football players.

DOI：
10.1007/s00259-022-05963-x
发表时间：
2023-01
期刊：
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
影响因子：
9.1
作者：
Alosco, Michael L.;Su, Yi;Stein, Thor D.;Protas, Hillary;Cherry, Jonathan D.;Adler, Charles H.;Balcer, Laura J.;Bernick, Charles;Pulukuri, Surya Vamsi;Abdolmohammadi, Bobak;Coleman, Michael J.;Palmisano, Joseph N.;Tripodis, Yorghos;Mez, Jesse;Rabinovici, Gil D.;Marek, Kenneth L.;Beach, Thomas G.;Johnson, Keith A.;Huber, Bertrand Russell;Koerte, Inga;Lin, Alexander P.;Bouix, Sylvain;Cummings, Jeffrey L.;Shenton, Martha E.;Reiman, Eric M.;McKee, Ann C.;Stern, Robert A.
通讯作者：
Stern, Robert A.

Tau Pathology in Chronic Traumatic Encephalopathy is Primarily Neuronal.