Candidate: I am a Neurocritical Care Neurologist and Assistant Professor of Neurology at Yale. My career goal is to become an independent physician-scientist and gerontologist whose research focuses on integrating genomic, neuroimaging and outcomes data to identify novel biological mechanisms and therapeutic targets in cerebral small vessel disease (CSVD). My clinical training in neurocritical care and doctoral training in genetic epidemiology have prepared me to pursue this path. I have a track record of early success, as evidenced by several impactful original publications and receipt of two competitively awarded grants, including a Yale Pepper Scholar Award. I have also distinguished myself as a national and international leader in cerebral small vessel disease genomics: I am the inaugural early career member of the International Stroke Genetics Consortium Steering Committee and co-Chair of the Cerebrovascular Disease Knowledge Portal?s operations committee. Mentors and Environment: My mentoring team is formed by international leaders in their respective fields: David Hafler (Population Genetics), Chair of Neurology; Thomas Gill (Geriatrics and Outcomes), Director of the Yale Program on Aging/Pepper Center; Murat Gunel (Stroke Genomics), Chair of Neurosurgery; Kevin Sheth (Neuroimaging Phenotypes), Division Chief of Neurocritical Care; and Ronald Coifman (Statistical Modeling), Professor of Mathematics. The proposed research and career development plans draw on the wealth of resources available at Yale, including the Program on Aging, Program on Neurogenetics and the School of Public Health, as well as the practical experience offered by the Hafler and Gunel Labs. I will train in the analysis of sequencing and neuroimaging data, machine learning tools, cloud computing resources and outcomes research. Mentored Research: By contributing or directly leading to several age-related conditions, CSVD poses a heavy burden on older persons. Intracerebral hemorrhage (ICH) constitutes the most severe manifestation of CSVD. Because no effective treatments are available, 60% of ICH patients die or remain severely disabled. Genetic analyses constitute a powerful tool to identify novel biological pathways and therapeutic targets in ICH because genetic variation contributes substantially to its risk. However, it remains unknown whether this genetic influence extends beyond risk to also influence radiological severity and subsequent outcomes. We will utilize 10,346 scans from 3,434 patients enrolled in 5 genetic studies of ICH to: (1) develop an open-source neuroimaging pipeline based on machine learning to automatically quantify neuroimaging markers of ICH severity; (2) identify genetic determinants of radiological severity; and (3) evaluate the role of identified risk loci on clinical outcomes and long-term health status. The proposed research will generate a valuable open access neuroimaging tool and will identify novel biological pathways linked to severity and outcomes in ICH. Because CSVD-related conditions have substantial biological overlap, our discoveries will have important applications to other diseases of aging, including vascular dementia, small vessel ischemic stroke, parkinsonism and gait disorders.
Spontaneous intracerebral hemorrhage constitutes the most severe manifestation of cerebral small vessel disease: 30% of patients die during hospital admission and an additional 30% remain severely disabled. The proposed research combines genomic and neuroimaging analyses to identify genetic risk factors involved in the severity, short term functional outcomes and long-term health status of intracerebral hemorrhage. Genetic factors identified by this proposal will point to previously unrecognized biological mechanisms that could be targeted by novel preventive, treatment and rehabilitation strategies for intracerebral hemorrhage as well as other diseases linked to cerebral small vessel disease, including small vessel ischemic stroke and vascular dementia.
