BLR&D Research Career Scientist Award Application

James J Peters Va Medical Center, Bronx NY

Investigators

Abstract

For over a decade and a half, Dr. Dracheva, the Principal Investigator (PI), has strategically centered her work on uncovering the molecular underpinnings of central nervous system (CNS) disorders common among U.S. military Veterans. These encompass psychiatric and neurological disorders, such as major depression disorder (MDD) and suicide, schizophrenia (SZ), opioid addiction, as well as amyotrophic lateral sclerosis (ALS) and spinal cord injury. The existing treatments for these disorders are extremely limited and often ineffective for a large subset of patients, hence there is a strong need to advance our understanding of their biological basis to develop novel more efficacious medications. The essence of the PI’s approach lies in deciphering how genetic and epigenetic mechanisms orchestrate gene expression in the healthy brain and identifying malfunctions leading to disorders. Her multidisciplinary research integrates insights from genetics, epigenetics, molecular biology, neural development, and evolution. The PI’s research has made significant contributions to the field, both conceptually and methodologically. For example, her studies identified unique molecular markers associated with suicide, that are distinct from those related to underlying psychiatric conditions, e.g., MDD or bipolar disorders. She also discovered a unique human component to vulnerability towards opioid addiction, highlighting the limitations of animal models and underscoring the necessity of studying opioid addiction in the human brain, as practiced in her laboratory. These findings are particularly relevant to U.S. Veterans, who exhibit significantly higher rates of suicide and opioid overdose mortality compared to civilians. Methodologically, her lab champions cell-type- specific experimental methods, considering the brain's cellular diversity. This innovative strategy deepens our understanding of disease mechanisms and the complexities of brain disorders. The PI’s pioneering methods and insights have been adopted by numerous laboratories, leading to high-impact collaborative research. In this application, the PI seeks a VA BLR&D Research Career Scientist (RCS) Award based on her important contributions to research, collaborations, training, editorial work, and administration, both inside and outside the VA. Her accomplishments are evident from a steady stream of publications in reputable journals, grant awards (VA Merit and NIH grants), mentorships, membership in editorial boards (Science Reports, Frontiers in Pharmocol, and Frontiers in Neuroscience), ad hoc reviewer’s assignments for numerous journals, intramural committee appointments at her VA, and extramural work as a grant reviewer for VA, NIH, and foundations. Dr. Dracheva is a founding member of the PsychEncode Consortium that generates large scale transcriptional and epigenetic data on tissues and cells from healthy and diseased human postmortem brains, including from patients with post-traumatic stress disorder (PTSD), MDD, and SZ, which are highly prevalent in U.S. Veterans. These data are shared with the scientific community to accelerate the discoveries on the molecular pathophysiology of these disorders. Impact: To the best of our knowledge, the PI’s current VA Merit grants are the first studies to elucidate the role of microglia in pathophysiology of MDD and to identify brain cell-type-specific markers associated with a slower progression of ALS. Her future research efforts in the VA include investigating the molecular basis of opioid addiction at a single cell level and dysregulation of DNA hydroxymethylation in the brain of suicide victims. The RCS Award will enable PI to broaden her research scope and establish new collaborations. These research efforts will significantly enhance our comprehension of the neurobiology of brain disorders, and more importantly, pave the way for the discovery of innovative therapeutic targets, thereby addressing the prevailing brain disorders among Veterans with greater efficacy.