Neurotrophic Factor Signaling in the Pathogenesis of HIV-associated Depression: Cohort and Mechanistic Studies

摘要 神经营养因子信号在HIV相关性抑郁症发病机制中的作用：队列和 机械学研究 众所周知，艾滋病毒携带者的抑郁会恶化艾滋病毒的结果和生活质量。之前 研究表明脑源性神经营养因子(BDNF)在神经元发育中起关键作用 和维持，在抑郁症中很重要。为了更好地了解心绞痛的病理生理学 我们希望利用蛋白质组学来进一步研究BDNF通路在HIV感染前的作用 现有的HIV感染者的脑脊液样本，然后在小鼠HIV上进行概念验证测试 抑郁症的模型。 我们可以从一项研究中收集的门诊艾滋病毒患者的脑脊液中获得 HIV相关神经认知障碍的脑脊液检查及临床资料收集 好几年了。评估包括神经认知测试和该中心的抑郁症筛查 用于流行病学研究的抑郁症(CESD)。我们计划进行发现和验证 蛋白质组学，重点是验证BDNF途径的蛋白质组学。我们将使用 机器学习分析计划将我们的蛋白质组学结果与CESD进行总体比较和 在项目级的基础上，以及使用NIMH研究领域的认知评估 标准(RDoC)结构，重点关注损失、回报、估值和认知。我们计划做的是 这一分析首先是横向的，然后通过纵向比较进一步验证。我们 假设脑脊液神经营养因子BDNF与神经炎性标志物相关 有抑郁症状；与抑郁症状的联系强度在 持续神经炎的RDoC域与持续的症状密切相关。 我们计划将我们的蛋白质组学研究结果用于HIV抑郁的小鼠模型。 在脑源性神经营养因子途径上。我们计划获得人源化的小鼠，并让一半的小鼠感染艾滋病毒。我们会 评估他们是否患有抑郁症，然后给其中一半注射BDNF拮抗剂，然后再进行评估 进行标准的抑郁测试。我们假设接受治疗的小鼠会表现出更多的 抑郁比未治疗的小鼠(更少的蔗糖偏好，更少的社交，更少的静止 时间)，因为BDNF提高了弹性和神经可塑性。 成功完成将在BDNF途径上产生有影响的数据，并可能发现 艾滋病毒相关性抑郁症的其他治疗目标。

Abstract Neurotrophic Factor Signaling in the Pathogenesis of HIV-associated Depression: Cohort and Mechanistic Studies Depression in people with HIV is known to worsen HIV outcomes as well as quality of life. Prior studies have shown Brain Derived Neurotrophic Factor (BDNF) is pivotal in neuron development and maintenance and important in depression. To better understand the pathophysiology of depression in HIV, we desire to use proteomics to further study the BDNF pathways in pre- existing CSF samples from people with HIV and then do a proof-of-concept test in a murine HIV model of depression. We have access to cerebrospinal fluid from a cohort of outpatients with HIV collected in a study of HIV-associated Neurocognitive Disorders with CSF and clinical data collection at 0 and 2 years. The evaluation included neurocognitive testing and depression screening with the center for epidemiological studies depression (CESD). We plan to do discovery and validation proteomics with focus in the validation proteomics for the BDNF pathway. We will use a machine-learning analysis plan comparing our proteomics findings with the CESD generally and on an item-level basis as well as cognitive evaluations using the NIMH Research Domain Criteria (RDoC) constructs with focus on Loss, Reward Valuation, and Cognition. We plan to do this analysis first cross-sectionally and then further validate by comparing longitudinally. We hypothesize CSF neurotrophic factor BDNF with neuroinflammatory markers are associated with depressive symptoms; strength of association with depressive symptoms will vary within RDoC domains with persistent neuroinflammation closely tied to ongoing symptoms. We plan to use our findings from proteomics in an HIV murine model of depression with focus on the BDNF pathways. We plan to acquire humanized mice and infect half with HIV. We will evaluate them for depression and then inject half with a BDNF antagonist and evaluate again with standard depression testing. We hypothesize the treated mice to exhibit more signs of depression than untreated mice (less sucrose preference, less social interaction, less immobile time) as BDNF improves resilience and neuroplasticity. Successful completion will yield impactful data on the BDNF pathways and could discover additional targets for treatment of HIV-associated depression.