The applicant, Aliza Wingo, M.D., M.Sc., is a board-certified psychiatrist and principal investigator at the Atlanta VA Medical Center. The first focus of Dr. Wingo’s research is to identify the genetic and molecular contributors to psychological resilience, PTSD, and depression, respectively. She is keenly aware of the complex relationships among these three facets of mental condition and also works to identify common and distinct mechanisms among them. The second focus of Dr. Wingo’s work is to identify how resilience, PTSD, and depression share common genetic and molecular basis with Alzheimer’s disease dementia. Through studying psychological constructs, she aims to identify novel pathways for enhancing resilience, treating PTSD/depression, and identifying novel causes of Alzheimer’s dementia that could be leveraged for new therapies. This work is currently supported by a Merit Review award from the VA, an R01 from the NIA/NIH, and a U01 from the NIMH/NIH. With regard to resilience, Dr. Wingo has shown that a genetic variant on chromosome 1 (rs322931) and brain expression level of miR-181 contribute to resilience (Wingo et al, Molecular Psychiatry, 2016). Resilience here is conceptualized as having high levels of positive emotions and/or sense of life purpose and meaning after adverse or traumatic life experiences. In her current funded Merit Review, Dr. Wingo examines brain microRNA profile to identify a microRNA signature of resilience. Next, she will use systems biology approach to identify brain transcriptomic drivers of resilience using brain transcriptome. Finally, she will examine the mRNAs and proteins that are downstream targets of the resilience-associated microRNAs with the overall goal of identifying novel genes regulating resilience. Regarding PTSD and depression, Dr. Wingo has shown that DICER1 and microRNA regulation pathway contributes to PTSD and depression (Wingo et al, Nature Communications, 2016). In this CDTA, Dr. Wingo proposes to harness deep human brain proteomes quantified by mass spectrometry from post-mortem brain tissues as a reference to impute brain protein expression level in Veterans who have genotyping. The imputed protein expression profile is then used for a proteome-wide association study of PTSD and depression, respectively, to identify proteins in the brain that predispose to PTSD or depression. In addition, epidemiological studies have observed that offspring of pregnant women suffering from PTSD or depression have higher risk for developing psychological or behavioral issues later in life. To investigate the mechanisms behind this intergenerational association, Dr. Wingo has been funded by a U01 to examine offspring’s blood- based transcriptome and global microRNA profile. These findings are highly relevant to female Veterans who suffer higher risk for PTSD and depression. Regarding dementia, Dr. Wingo has shown that hundreds of proteins in human brain are altered with cognitive decline in advanced a...