BLR&D Research Career Development Transition Award Application

申请人Aliza Wingo医学博士理学硕士，是一名委员会认证的精神病学家和首席研究员， 亚特兰大退伍军人医疗中心Wingo博士研究的第一个重点是确定遗传和分子 心理弹性，创伤后应激障碍和抑郁症的贡献者。她敏锐地意识到， 复杂的关系，这三个方面的精神状况，也工作，以确定共同的， 不同的机制。Wingo博士工作的第二个重点是确定恢复力，PTSD， 和抑郁症与阿尔茨海默病痴呆症有着共同的遗传和分子基础。通过 研究心理结构，她的目标是确定新的途径，以提高弹性，治疗 创伤后应激障碍/抑郁症，并确定阿尔茨海默氏症痴呆症的新原因，可以利用新的 治疗这项工作目前得到了VA的Merit Review奖，NIA/NIH的R 01， 和NIMH/NIH的U 01。 关于恢复力，Wingo博士已经表明，1号染色体上的遗传变异（rs322931）和 miR-181的脑表达水平有助于恢复（Wingo等人，Molecular Psychiatry，2016）。复原力 这里被概念化为具有高水平的积极情绪和/或生活目的和意义感 在经历了痛苦或创伤后在她目前资助的Merit Review中，Wingo博士检查了大脑 microRNA图谱来识别恢复力的microRNA特征。接下来，她将使用系统生物学方法， 使用脑转录组识别复原力的脑转录组驱动因素。最后，她将检查 mRNA和蛋白质是毒性相关microRNA的下游靶点， 找到调节恢复力的新基因。 关于创伤后应激障碍和抑郁症，Wingo博士已经表明，DICER 1和microRNA调节 途径导致PTSD和抑郁症（Wingo et al，Nature Communications，2016）。在这篇文章中，博士。 Wingo建议利用死后的质谱定量人脑深层蛋白质组， 脑组织作为参考，以估算具有基因分型的退伍军人的脑蛋白表达水平。的 然后将估算的蛋白质表达谱用于PTSD的蛋白质组范围关联研究， 抑郁症，以确定大脑中易患PTSD或抑郁症的蛋白质。此外，本发明还提供了一种方法， 流行病学研究发现，患有创伤后应激障碍或抑郁症的孕妇的后代 在以后的生活中出现心理或行为问题的风险更高。为了研究 在这种代际关联的背后，Wingo博士得到了U 01的资助，检查后代的血液， 基于转录组和全球microRNA谱。这些发现与女性退伍军人高度相关， 患创伤后应激障碍和抑郁症的风险更高。 关于痴呆症，Wingo博士已经表明，人类大脑中的数百种蛋白质会随着年龄的增长而改变。 老年认知能力下降（Wingo et al，Nature Communications，2019）。由于大流行病 研究发现，抑郁症，尤其是晚年抑郁症，会增加患痴呆症的风险。 Wingo由R 01资助，旨在阐明抑郁症有害影响的分子机制 使用死后多组学数据研究生活目的对阿尔茨海默氏痴呆风险的保护作用 脑组织 通过研究遗传和分子机制， 创伤后应激障碍，抑郁症和阿尔茨海默氏痴呆症，Wingo博士希望 有助于促进我们对其病因的理解，以开发新颖有效的干预措施。作为 长期目标，Wingo博士渴望进行新颖和创新的研究问题，使变革 影响我们退伍军人的健康和恢复力。

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 age (Wingo et al, Nature Communications, 2019). Since large epidemiological studies have observed that depression, especially late-life depression, increases the risk for dementia, Dr. Wingo is funded by an R01 to elucidate molecular mechanisms underlying detrimental effects of depression and protective effects of life purpose on Alzheimer’s dementia risk using multi-omics data from post-mortem brain tissues. Through studying the genetic and molecular mechanisms underlying the conditions that disproportionally affect our Veterans – PTSD, depression, and Alzheimer’s dementia, Dr. Wingo hopes to contribute to advancing our understanding of their etiologies to develop novel and effective interventions. As a long-term goal, Dr. Wingo aspires to carry out novel and innovative research questions to make transformative impact on the health and resilience of our Veterans.