BLR&D Research Career Development Transition Award Application

BLR

• 批准号: 10514573
• 负责人: Aliza Pham Wingo
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514573
• 关键词: Address; Affect; Alzheimer' s Disease; Anxiety; Area; Autopsy; Award; Awareness; Behavioral; Biological Models; Biological Psychiatry; Blood; Board Certification; Brain; Caring; Chromosome 1; Cognitive; Communication; Complex; DICER1 gene; Data; Data Set; Dementia; Development; Doctor of Medicine; Elderly; Etiology; Event; Female; Formulation; Funding; Future; Genes; Genetic; Genetic study; Genomic medicine; Genotype; Goals; Health; Healthcare; Human; Impaired cognition; Individual; Intervention; Journals; K-Series Research Career Programs; Life; Life Experience; Mass Spectrum Analysis; Meaning and purpose; Medical center; Mental Depression; Messenger RNA; Meta-Analysis; MicroRNAs; Modeling; Molecular; Multiomic Data; National Institute of Mental Health; Nature; Neurobiology; Outcome; Paper; Participant; Pathway interactions; Patient Care; Post-Traumatic Stress Disorders; Prefrontal Cortex; Pregnant Women; Principal Investigator; Proteins; Proteome; Proteomics; Psyche structure; Psychiatrist; Psychiatry; Publications; Publishing; Regulation; Research; Research Personnel; Research Priority; Role; Seminal; Shapes; Stress; Symptoms; Systems Biology; Techniques; Transition Career Development Award (K22); Translating; Trauma; United States National Institutes of Health; Veterans; Weight; Woman; Work; brain tissue; career; comorbid depression; coping; dementia risk; effective intervention; epidemiology study; experience; genetic variant; genome wide association study; geriatric depression; high risk; innovation; intergenerational; mRNA Expression; multiple omics; novel; novel therapeutic intervention; novel therapeutics; offspring; positive emotional state; programs; promote resilience; protective effect; protein expression; psychologic; resilience; statistics; transcriptome; transcriptomics

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.

申请人Aliza Wingo，M.D。，M.Sc。是董事会认证的精神科医生和首席研究员 亚特兰大弗吉尼亚州医疗中心。 Wingo博士研究的第一个重点是识别遗传和分子 分别为心理弹性，PTSD和抑郁症的贡献者。她敏锐地意识到 精神状况的这三个方面之间的复杂关系，还致力于确定常见和 其中的不同机制。 Wingo博士工作的第二个重点是确定PTSD的弹性如何 抑郁症与阿尔茨海默氏病痴呆具有共同的遗传和分子基础。通过 她研究心理结构，旨在确定增强弹性，治疗的新颖途径 PTSD/抑郁症，确定可以利用新的阿尔茨海默氏症的新原因 疗法。目前，这项工作得到了VA的优异审查奖，NIA/NIH的R01， 和NIMH/NIH的U01。 关于弹性，Wingo博士表明，染色体1（RS322931）和 miR-181的大脑表达水平有助于韧性（Wingo等人，分子精神病学，2016年）。弹力 这被概念化为具有高水平的积极情绪和/或生活意义和意义 经过不利或创伤的生活经历。 Wingo博士在她目前的资助优异评论中大脑 microRNA曲线以识别弹性的microRNA签名。接下来，她将使用系统生物学方法来 使用脑转录组确定脑部转录组的弹性驱动因素。最后，她将检查 与弹性相关的microRNA的下游靶标的mRNA和蛋白质具有总体目标 鉴定新基因的弹性。 关于PTSD和抑郁症，Wingo博士表明DICER1和MicroRNA调节 途径有助于PTSD和抑郁症（Wingo等人，自然通讯，2016年）。在此CDTA中，博士 WINGO提出的利用深人脑蛋白质通过后质谱法量化的深人脑蛋白 脑组织是指具有基因分型的退伍军人的脑型脑蛋白表达水平。这 然后将估算的蛋白质表达谱用于PTSD和PTSD蛋白质组的关联研究 抑郁症分别鉴定出易感PTSD或抑郁症的大脑中的蛋白质。此外， 流行病学研究观察到，患有PTSD或抑郁症的孕妇的后代 在以后的生活中，患有心理或行为问题的风险更高。调查机制 在这个代际协会的背后，Wingo博士由U01资助，以检查后代的血液 - 基于转录组和全局microRNA概况。这些发现与女性退伍军人高度相关 患有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随着 高级年龄的认知能力下降（Wingo等人，自然通讯，2019年）。自大流行病学 研究观察到，抑郁症，尤其是晚期抑郁症会增加痴呆症的风险，博士。 Wingo由R01资助，以阐明抑郁症的有害影响的分子机制 使用验尸中的多摩尼斯数据对生命目的的影响对阿尔茨海默氏症的痴呆症风险 脑组织。 通过研究研究条件的遗传和分子机制 Wingo博士希望对我们的退伍军人 - PTSD，抑郁症和阿尔茨海默氏症的痴呆症的痴呆症造成不成比例的影响 有助于促进我们对他们的病因的理解，以开发新颖有效的干预措施。作为 长期目标，Wingo博士渴望提出新颖而创新的研究问题，以使变革性 对我们退伍军人的健康和韧性的影响。