BLR&D Research Career Development Transition Award Application

申请人Aliza Wingo，M.D.，M.SC，是委员会认证的精神病学家和 亚特兰大退伍军人医疗中心。Wingo博士研究的第一个重点是识别基因和分子 分别是心理韧性、创伤后应激障碍和抑郁症的贡献者。她敏锐地意识到 精神状态的这三个方面之间的复杂关系，也致力于识别共同和 它们之间有着截然不同的机制。Wingo博士工作的第二个重点是确定弹性、创伤后应激障碍、 抑郁症与阿尔茨海默病痴呆症有着共同的基因和分子基础。穿过 通过研究心理结构，她的目标是找到增强韧性、治疗 创伤后应激障碍/抑郁，并确定阿尔茨海默氏症的新原因，可用于新的 治疗。这项工作目前由退伍军人事务部颁发的功绩审查奖、NIA/NIH颁发的R01奖、 以及来自NIMH/NIH的U01。 关于韧性，Wingo博士已经证明了1号染色体上的一个遗传变异(Rs322931)和 MiR-181的脑表达水平有助于弹性(Wingo等人，分子精神病学，2016)。恢复力 这里被概念化为具有高度的积极情绪和/或对生活目标和意义的感觉 在经历了不利的或创伤性的生活经历之后。在她目前资助的功绩评估中，Wingo博士检查了大脑 MicroRNA图谱，以确定弹性的microRNA签名。接下来，她将使用系统生物学的方法来 使用大脑转录组识别大脑转录驱动的弹性。最后，她将审查 作为韧性相关microRNAs下游目标的mRNAs和蛋白质，总体目标 识别调节韧性的新基因。 关于创伤后应激障碍和抑郁症，Wingo博士已经证明DICER1和microRNA调节 路径导致创伤后应激障碍和抑郁症(Wingo等人，《自然通讯》，2016)。在这份CDTA中，Dr。 Wingo建议利用死后质谱学定量的人脑深层蛋白质组 以脑组织作为参考，推测具有基因分型的退伍军人脑蛋白表达水平。这个 然后使用推测的蛋白质表达谱进行蛋白质组范围的PTSD和 抑郁症，分别识别大脑中易患创伤后应激障碍或抑郁症的蛋白质。此外, 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 在以后的生活中有更高的心理或行为问题的风险。探讨其作用机制 在这种代际联系的背后，温戈博士得到了一台U01的资助，以检查后代的血液-- 基于转录组和全球microRNA图谱。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，温戈博士已经证明，人类大脑中的数百种蛋白质会随着 老年认知衰退(Wingo等人，《自然通讯》，2019年)。由于大规模的流行病 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R01资助，以阐明抑郁症有害影响的分子机制 用尸检多组学数据研究生活目的对阿尔茨海默病风险的保护作用 脑组织。 通过研究这种情况背后的遗传和分子机制 不成比例地影响我们的退伍军人--创伤后应激障碍、抑郁症和阿尔茨海默氏症，温戈博士希望 有助于促进我们对其病因的理解，以开发新的有效干预措施。作为一名 长期目标，Wingo博士渴望进行新颖和创新的研究问题，使之具有变革性 对我们退伍军人的健康和韧性的影响。

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.