Immunometabolicgene expression profiles associated with depressed mood and behavioral domains inpeople with HIV

与艾滋病毒感染者抑郁情绪和行为领域相关的免疫代谢基因表达谱

• 批准号: 10643884
• 负责人: RONALD J. ELLIS
• 金额: $ 69.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643884
• 关键词: Abbreviations; Age; Anhedonia; Animal Behavior; Animal Model; Animals; Antidepressive Agents; Beck depression inventory; Behavior; Behavioral; Biological Markers; Biometry; Brain; Caring; Cells; Clinical; Clinical Data; Clinical Research; Cognitive; Collaborations; Complex; Data; Depressed mood; Epidemic; Estradiol; FRAP1 gene; Family; Female; Functional disorder; Future; Gene Expression; Genes; Genomics; Gonadal Steroid Hormones; HIV; HIV Infections; Health; High Prevalence; Human; Immune; Immunity; Immunology; Individual; Inflammasome; Inflammation; Inflammatory; Knowledge; Link; Literature; Machine Learning; Major Depressive Disorder; Mediating; Mental Depression; Metabolic Marker; Metabolism; Microglia; Modeling; Molecular; Molecular Biology; Mood Disorders; Mus; Neurologist; Neurosciences; Outcome; Pathway interactions; Persons; Population; Predisposition; Premenopause; Proteins; Psychophysiology; Research; Research Domain Criteria; Research Personnel; Resistance; Role; Sampling; Severities; Sex Differences; Signal Transduction; Testosterone; Translational Research; Viral; Woman; Work; adverse outcome; biological research; brain tissue; clinically significant; cognitive process; depressive symptoms; effective therapy; experience; health related quality of life; immune function; inflammatory marker; inhibitor; innovation; male; marenostrin; men; monocyte; mouse model; neurobehavior; protein expression; recruit; sex; single-cell RNA sequencing; transcriptome; transcriptome sequencing; transcriptomics; translational approach; virology

SUMMARY This project will leverage emerging knowledge about the role of immunometabolism in the pathophysiology of depression in people with HIV to generate hypotheses about potential future treatments. Depression in PWH is characterized by features that differentiate it from depression in people without HIV (PWoH). The first is the predominance of anhedonia - inability to gain enjoyment from activities. The second is a higher prevalence of depression that is resistant to treatment with standard antidepressant drugs in PWH versus PWoH. These clinical observations suggest not only that the underlying pathophysiology of depression is different between the two populations, but that different treatments are needed to successfully treat depression in PWH. Molecular studies of immunometabolism, defined as reciprocal interactions between immunity and metabolism that are dysregulated and linked to depression in PWH, support these distinctions. Based on our preliminary data and that in the literature, we propose to perform RNA-Seq transcriptomics, relating immunometabolic gene expression to protein and other biomarkers of immunometabolism, and to clinical depression as well as to cognitive processes impacted by depression. Our hypothesis-driven approach will focus on two interacting, co-regulated gene pathways central to depression and immunometabolism, the mammalian target of rapamycin (mTOR) and the NLRP3 inflammasome. We will study 80 newly recruited PWH and 40 age- matched PWoH. Given our early work suggesting that the relationship between immunometabolism and depression is sex-dependent, we aim for a 50/50 breakdown of men and premenopausal women in order to examine sex differences in these relationships. To optimize the spectrum of depressive symptom severity in our sample (e.g., avoid over-representation of individuals with minimal depressive symptoms), we will stratify with a 50/50 breakdown above and below the previously established Beck Depression Inventory-II cut-score for clinically-significant depressive symptoms (≥16). Since clinical studies cannot rigorously establish mechanistic relationships, we will study in parallel the roles of mTOR and NLRP3 inflammasome signaling in depression-like behaviors in a mouse model of HIV infection, EcoHIV, which expresses seven of nine key human HIV proteins. These pathways will be dissected using mTOR and NLRP3 inhibitors. Also, in these animals we will characterize immunometabolic markers in brain tissue, presumably the substrate of depression.

总结 该项目将利用新兴的知识，免疫代谢的作用，在病理生理学的 研究HIV感染者的抑郁症，以产生关于未来潜在治疗的假设。威尔斯亲王医院的抑郁症 其特征在于将其与无艾滋病毒的人的抑郁症（PWoH）区分开来。首先是 快感缺乏的优势-无法从活动中获得乐趣。第二个是更高的患病率， PWH与PWoH中对标准抗抑郁药物治疗耐药的抑郁症。这些 临床观察表明，不仅抑郁症的基础病理生理学不同， 这两个群体，但不同的治疗需要成功地治疗抑郁症的PWH。 免疫代谢的分子研究，定义为免疫和代谢之间的相互作用 与威尔斯亲王医院的抑郁症有关的失调的基因支持了这些区别。根据我们初步的 数据和文献中，我们建议进行RNA-Seq转录组学， 基因表达到蛋白质和其他免疫代谢生物标志物，以及临床抑郁症， 抑郁症对认知过程的影响我们的假设驱动的方法将集中在两个相互作用， 共同调节的基因通路中央抑郁症和免疫代谢，哺乳动物的目标， 雷帕霉素（mTOR）和NLRP 3炎性体。我们会研究80名新入职的威尔斯亲王医院及40名年龄介乎- 匹配PWoH。鉴于我们早期的工作表明，免疫代谢和 抑郁症是性别依赖性的，我们的目标是男性和绝经前女性各占50/50， 研究这些关系中的性别差异。优化抑郁症状严重程度谱， 我们的样本（例如，避免过度代表的个人与最小的抑郁症状），我们将分层 在先前建立的Beck抑郁量表-II的分界分数之上和之下各占50/50 临床显著抑郁症状（≥16）。由于临床研究不能严格确定 机制的关系，我们将平行研究mTOR和NLRP 3炎性体信号转导在 HIV感染小鼠模型EcoHIV中的抑郁样行为，表达了九个关键基因中的七个。 人HIV蛋白。将使用mTOR和NLRP 3抑制剂剖析这些途径。此外，在这些 我们将描述动物脑组织中的免疫代谢标志物，推测为 萧条