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

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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.