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

父母补助金摘要 重性抑郁障碍（MDD）是精神科最具异质性的疾病之一， 治疗对大多数患者来说是不够的，可能是因为它们没有针对个体的亚型。 提高我们对MDD亚型的理解将使我们能够（1）确定针对亚型特异性的治疗方法， 病理生理学和（2）确定哪个MDD患者亚组对这些治疗反应最好，因此 改善抗抑郁药的疗效。在神经炎性亚型中，MDD可通过慢性炎症反应表现出来。 神经炎症转运蛋白（TSPO）位于小胶质细胞线粒体外膜， 和星形胶质细胞，被认为是这种神经炎症的标志物，并且可以在体内通过正电子 发射断层扫描（PET）。为了支持MDD的神经炎性亚型，通过PET测量的TSPO， 在MDD患者的前额叶皮层（PFC）中，相对于健康个体，平均升高了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，显示PFC升高 TSPO和其他升高的神经炎症标志物在一个子集的“抑郁”，非弹性小鼠， 通过消除表达TSPO的神经胶质细胞逆转表型！为了在人类中模拟这种效应，大脑- 可以使用渗透性抗炎药物如塞来昔布。塞来昔布具有抗抑郁作用 然而，观察到的效应量是高度可变的，可能反映了MDD的生物异质性。 MDD。我们推测，抗炎治疗如塞来昔布对那些有 抑郁症的神经炎症亚型，抗抑郁药的作用机制是通过减少 神经炎症我们将在人类和啮齿动物的平行研究中检验这些假设。为人类 目的是，我们将利用目前正在斯托尼布鲁克进行的塞来昔布疗效研究 医学（PI：Parsey）通过招募已经接受塞来昔布治疗的参与者（8周， 400 mg/天）。将入组53例MDD受试者，预计42例将完成涉及TSPO PET的研究 治疗前后的影像学检查。我们假设，较高的PFC TSPO（通过PET测量）之前， 治疗将与塞来昔布更好的反应相关，而且PFC TSPO的降低将 在调整协变量后与抑郁改善相关。在啮齿动物的平行研究中，我们 假设在我们反复社交失败应激小鼠中PFC TSPO和其它CNS炎症标记物 通过microPET、定量蛋白质/mRNA水平分析和 反应性小胶质细胞形态，与野生型小鼠相比。此外，我们假设PFC升高 塞来昔布治疗后，TSPO和其他神经炎症标志物将减少。如果小鼠和人类 研究不同意，这表明TSPO PET提供了神经炎症的临床相关代理。 然而，如果我们的假设得到证实，这将证实TSPO是神经炎症的标志物， MDD亚型和治疗目标。

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.