BLR&D Research Career Development Transition Award Application

申请人 Aliza Wingo，医学博士、理学硕士，是一名经过委员会认证的精神病学家，也是该机构的首席研究员。 亚特兰大退伍军人管理局医疗中心。 Wingo 博士研究的首要重点是确定遗传和分子 分别影响心理弹性、创伤后应激障碍和抑郁症。她敏锐地意识到 精神状况的这三个方面之间的复杂关系，并努力识别共同点和 其中机制各异。 Wingo 博士工作的第二个重点是确定复原力、创伤后应激障碍 (PTSD) 如何 抑郁症与阿尔茨海默病痴呆具有共同的遗传和分子基础。通过 通过研究心理结构，她的目标是找到增强复原力、治疗疾病的新途径 PTSD/抑郁症，并确定阿尔茨海默氏痴呆症的新原因，这些原因可用于新的治疗 疗法。这项工作目前得到了 VA 的优异评审奖、NIA/NIH 的 R01 奖的支持， 以及来自 NIMH/NIH 的 U01。 关于复原力，Wingo 博士表明，1 号染色体上的遗传变异 (rs322931) 和 miR-181 的大脑表达水平有助于恢复能力（Wingo 等人，分子精神病学，2016）。韧性 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 在经历了不利或创伤性的生活经历之后。温戈博士在她目前资助的优异评审中检查了大脑 microRNA 谱来识别恢复力的 microRNA 特征。接下来，她将利用系统生物学方法 使用大脑转录组识别恢复力的大脑转录组驱动因素。最后，她将检查 mRNA 和蛋白质是弹性相关 microRNA 的下游目标，具有总体目标 识别调节弹性的新基因。 关于 PTSD 和抑郁症，Wingo 博士表明 DICER1 和 microRNA 调节 通路会导致 PTSD 和抑郁症（Wingo 等人，Nature Communications，2016）。在本次 CDTA 中，Dr. Wingo 提议利用尸检质谱法量化人类大脑深层蛋白质组 脑组织作为估算进行基因分型的退伍军人脑蛋白表达水平的参考。的 然后使用估算的蛋白质表达谱进行 PTSD 和 PTSD 的全蛋白质组关联研究 抑郁症，以识别大脑中易患创伤后应激障碍（PTSD）或抑郁症的蛋白质。此外， 流行病学研究发现，孕妇的后代患有创伤后应激障碍（PTSD）或抑郁症 在以后的生活中出现心理或行为问题的风险更高。研究机制 在这个代际协会的背后，Wingo 博士得到了 U01 的资助，用于检查后代的血液 - 基于转录组和全局 microRNA 谱。这些发现与女性退伍军人高度相关 患 PTSD 和抑郁症的风险更高。 关于痴呆症，Wingo 博士表明，人脑中的数百种蛋白质会随着 高龄认知能力下降（Wingo 等人，Nature Communications，2019）。由于流行病学规模大 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，博士说。 Wingo 由 R01 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标对阿尔茨海默氏痴呆风险的保护作用 脑组织。 通过研究潜在的遗传和分子机制 Wingo 博士希望对我们的退伍军人产生不成比例的影响——创伤后应激障碍 (PTSD)、抑郁症和阿尔茨海默氏痴呆症 有助于增进我们对其病因的理解，以制定新颖有效的干预措施。作为一个 长期目标，Wingo 博士渴望开展新颖和创新的研究问题，以实现变革 对退伍军人的健康和复原力的影响。

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.