A translational study of neuroinflammatory depression: Understanding mechanism and evaluation of a novel pharmacologic intervention - Diversity Administrative supplement for Kimberly Nnah

神经炎症性抑郁症的转化研究：了解新型药物干预的机制和评估 - Kimberly Nnah 的多样性行政补充

• 批准号: 10721922
• 负责人: Christine Delorenzo
• 金额: $ 7.06万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721922
• 关键词: Administrative Supplement; Aftercare; Anti-Inflammatory Agents; Antidepressive Agents; Astrocytes; Brain; Chronic; Data; Depressed mood; Disease; Disease remission; Enrollment; Evaluation; Functional disorder; Human; Individual; Inflammatory; Intervention; Major Depressive Disorder; Measures; Medicine; Mental Depression; Messenger RNA; Microglia; Morphology; Mus; Neuroglia; Outcome; Outer Mitochondrial Membrane; Participant; Pathology; Patient Recruitments; Patients; Pharmaceutical Preparations; Phenotype; Positron-Emission Tomography; Prefrontal Cortex; Proteins; Proxy; Psychiatry; Rodent; Stress; Subgroup; Testing; Wild Type Mouse; antidepressant effect; biological heterogeneity; celecoxib; clinically relevant; depression model; depressive symptoms; disorder subtype; improved; in vivo; inflammatory marker; microPET; mouse model; neuroinflammation; novel; parent grant; pharmacologic; response; social defeat; targeted treatment; translational study

Abstract of the parent grant Major depressive disorder (MDD) is one of the most heterogeneous disorders in psychiatry and first line treatments are inadequate for the majority of patients, likely because they do not target an individual’s subtype. Improving our understanding of MDD subtypes will allow us to (1) identify treatments that target subtype-specific pathophysiology and (2) determine which subgroup of MDD patients will best respond to these treatments, thus improving antidepressant outcomes. In a neuroinflammatory subtype, MDD may manifest via chronic neuroinflammation. The translocator protein (TSPO), located on the outer mitochondrial membrane of microglia and astrocytes, is regarded as a marker of this neuroinflammation and can be measured in vivo by positron emission tomography (PET). In support of a neuroinflammatory subtype of MDD, TSPO, measured by PET, was found to be elevated by 30% on average in the prefrontal cortex (PFC) in MDD relative to healthy individuals. Further, we have preliminary data from a repeated social defeat stress mouse model that shows elevated PFC TSPO and other elevated neuroinflammation markers in a subset of ‘depressed’, non-resilient mice, and that this phenotype is reversed by elimination of TSPO expressing glial cells! To parallel this effect in humans, brain- penetrant anti-inflammatory medications such as celecoxib can be used. Celecoxib has antidepressant effects in MDD; however, the observed effect sizes are highly variable, likely reflecting the biological heterogeneity of MDD. We hypothesize that anti-inflammatory treatments such as celecoxib will be most effective in those with the neuroinflammatory subtype of MDD and that the mechanism of antidepressant action is through a reduction of neuroinflammation. We will test these hypotheses in parallel studies in humans in rodents. For the human aim, we will take advantage of an ongoing study of celecoxib efficacy currently being performed at Stony Brook Medicine (PI: Parsey) by recruiting participants who are already being treated with celecoxib (8 weeks, 400mg/day). 53 MDD participants will be enrolled, with 42 expected to complete the study involving TSPO PET imaging before and after treatment. We hypothesize that higher PFC TSPO (as measured by PET) prior to treatment will be correlated with better response to celecoxib and further, that reductions in PFC TSPO will be correlated to depression improvement after adjusting for covariates. In a parallel study in rodents, we hypothesize that PFC TSPO and other CNS inflammation markers in our repeated social defeat stress mouse model of depression will be elevated as measured by microPET, quantitative protein/mRNA level analysis, and reactive microglial morphology, when compared to wild type mice. Further, we hypothesize that elevated PFC TSPO and other neuroinflammatory markers will be reduced after celecoxib treatment. If mouse and human studies do not agree, this suggests that TSPO PET provides a clinically relevant proxy of neuroinflammation. However, if our hypotheses are confirmed, this would validate that TSPO is a marker of the neuroinflammatory MDD subtype and a target of treatment.

母基金摘要 摘要重度抑郁障碍(MDD)是精神病学中异质性最强的疾病之一。 对于大多数患者来说，治疗是不够的，可能是因为它们没有针对个人的亚型。 提高我们对MDD亚型的理解将使我们能够(1)确定针对特定亚型的治疗 病理生理学和(2)确定哪一亚组的MDD患者对这些治疗效果最好，因此 改善抗抑郁药物的疗效。在神经炎性亚型中，MDD可能通过慢性 神经炎。位于小胶质细胞线粒体膜外膜的转运蛋白(TSPO) 和星形胶质细胞，被认为是这种神经炎症的标志，并可以在体内用正电子测量 发射断层扫描(PET)。为了支持MDD的一个神经炎性亚型，PET测量的TSPO是 与健康人相比，MDD患者前额叶皮质(PFC)的平均水平升高了30%。 此外，我们有来自反复社交失败应激小鼠模型的初步数据，该模型显示PFC升高 TSPO和其他升高的神经炎性标记物在一组‘抑郁’、无弹性的小鼠中，这一点 通过消除表达TSPO的神经胶质细胞来逆转表型！为了在人类身上产生类似的影响，大脑- 可以使用塞来昔布等渗透性抗炎药物。塞来昔布有抗抑郁作用 然而，在MDD中，观察到的效应大小是高度可变的，很可能反映了 MDD。我们假设，抗炎治疗，如塞来昔布，将对那些患有 MDD的神经炎性亚型和抗抑郁作用的机制是通过减少 神经炎的症状。我们将在人类啮齿动物的平行研究中检验这些假说。对于人类来说 目的，我们将利用石溪医院目前正在进行的塞来昔布疗效研究 药物(PI：PARSY)招募已经接受塞来昔布治疗的参与者(8周， 400毫克/天)。将有53名MDD参与者参加，其中42名预计将完成涉及TSPO PET的研究 治疗前后进行影像检查。我们假设较高的PFC TSPO(由PET测量)在 治疗将与对塞来昔布的更好反应相关，此外，PFC TSPO的减少将是 调整协变量后与抑郁改善相关。在一项对啮齿动物的平行研究中，我们 假设PFC、TSPO和其他中枢神经系统炎症标记物在我们反复的社会失败中应激小鼠 抑郁模型将通过microPET、定量蛋白质/mRNA水平分析和 反应性小胶质细胞形态，与野生型小鼠比较。此外，我们假设PFC的升高 塞来昔布治疗后TSPO等神经炎性标志物降低。如果老鼠和人类 研究不同意这一点，这表明TSPO PET提供了一种临床相关的神经炎症指标。 然而，如果我们的假设得到证实，这将证实TSPO是神经炎性疾病的标志 MDD亚型和治疗靶点。