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.

父母赠款的摘要 重度抑郁症（MDD）是精神病学和第一线中最异质的疾病之一 对于大多数患者而言，治疗不足，可能是因为他们不针对个人的亚型。 提高我们对MDD子类型的理解将使我们能够（1）确定针对亚型特异性的治疗方法 病理生理学和（2）确定哪些MDD患者的亚组最能对这些治疗做出反应，从而 改善抗抑郁剂结果。在神经炎性亚型中，MDD可能通过慢性表现出来 神经炎症。位于小胶质细胞的外部线粒体膜上的转运蛋白（TSPO） 星形胶质细胞被认为是这种神经炎症的标志物，可以通过正电子在体内测量 排放断层扫描（PET）。支持由PET测量的MDD的神经炎症亚型TSPO为 相对于健康个体，在MDD的前额叶皮层（PFC）中，发现平均升高30％。 此外，我们有来自重复的社交失败压力鼠标模型的初步数据，该模型显示了PFC的升高 TSPO和其他升高的神经炎症标志物在“抑郁症”，非弹性小鼠的子集中 通过消除TSPO表达神经胶质细胞来逆转表型！在人类中平行这种影响，大脑 可以使用渗透剂抗炎药（例如塞来昔布）。塞来昔布具有抗抑郁作用 在MDD中；但是，观察到的效应大小是高度可变的，可能反映了生物学异质性 MDD。我们假设抗炎治疗（例如塞来昔布）在患有 MDD的神经炎性亚型和抗抑郁作用的机理是通过还原 神经炎症。我们将在人类在啮齿动物中的平行研究中检验这些假设。对于人类 AIM，我们将利用正在进行的塞雷克氧基效率正在进行的研究 医学（PI：Parsey）是通过招募已经接受过塞勒克昔布治疗的参与者（8周， 400毫克/天）。将招募53名MDD参与者，预计42名参与者将完成涉及TSPO PET的研究 在处理前后成像。我们假设较高的PFC TSPO（按PET测量） 治疗将与对塞来昔布更好的反应相关，然后，PFC TSPO的减少将是 调整协变量后，与抑郁症的改善相关。在啮齿动物的平行研究中，我们 假设PFC ​​TSPO和其他CNS注入标记在我们反复的社交失败压力鼠标中 通过Micropet，定量蛋白/mRNA水平分析和 与野生型小鼠相比，反应性小胶质细胞形态。此外，我们假设PFC升高 塞来昔布治疗后，TSPO和其他神经炎症标记将降低。如果老鼠和人类 研究不同意，这表明TSPO PET提供了与临床相关的神经炎症代表。 但是，如果确认我们的假设，这将证明TSPO是神经炎症的标志 MDD亚型和治疗的靶标。