Role of Kynurenine Pathway Metabolites in Perinatal Depression and Suicidality

描述(由申请人提供)：对围产期情绪障碍的生物学机制缺乏基本的了解，再加上缺乏适当的模型，阻碍了预防和治疗。因此，这项提案的目标是定义导致围产期抑郁的生物学过程，并找到可测量的结果，以确定谁有患上围产期抑郁症的风险。中心假说是，犬尿氨酸途径中一种关键酶活性不足的女性会因怀孕而出现抑郁和自杀倾向。在怀孕期间，胎盘中的犬尿氨酸途径分解色氨酸，将代谢物释放到血液中，在影响谷氨酸神经传递的同时对大脑产生后续影响。这一假说起源于强有力的初步数据，表明在有自杀念头的抑郁症患者中 犬尿氨酸代谢产物水平失调，会发生神经炎症，抑郁孕妇也有类似的倾向。这项研究的基本原理是，所提出的生物学机制为药物干预，靶向犬尿氨酸途径酶，以及开发围产期抑郁和自杀的生物标志物开辟了道路。在这项建议中，关键的犬尿氨酸途径酶及其下游代谢产物的水平和活性将在妊娠和产后妇女的胎盘、血液和单核细胞中进行测定。参与者将从在妇产科诊所就诊的社区人群以及密歇根州大急流城一项专门治疗产后自杀妇女及其婴儿的独特临床计划中招募。胎盘将在分娩时收集。所有研究参与者都将被仔细诊断和评估抑郁和自杀的精神症状以及危险因素。单核细胞和胎盘滋养层细胞将被培养，上清液和血液水平将使用气相色谱-质谱仪分析犬尿氨酸代谢物。结果将在两组生物库血浆和胎盘组织中得到验证，分别来自不同的地理位置。这项研究将确定围产期抑郁是否是抑郁症的一种不同的亚型，其病理生理机制类似于细胞因子诱导的抑郁症。这一发现可能导致识别围产期抑郁和自杀的新治疗靶点和生物标记物。

DESCRIPTION (provided by applicant): There is a fundamental lack of knowledge about the biological mechanisms underlying peripartum mood disorders, that combined with the lack of appropriate models hinders prevention and treatment. The goals of this proposal are therefore to define biological processes that cause peripartum depression and to find measurable outcomes that can be used to determine who is at risk of developing it. The central hypothesis is that women with a deficient activity of a key enzyme in the kynurenine pathway will develop depression and suicidality in response to pregnancy. During pregnancy, the kynurenine pathway in the placenta breaks down tryptophan, releasing metabolites into the blood that have subsequent effects on the brain as they affect glutamate neurotransmission. The hypothesis has its origin in strong preliminary data, showing that in depressed individuals with suicidal thoughts the levels of kynurenine-metabolites are dysregulated and neuroinflammation occurs, and a similar tendency in depressed pregnant women. The rationale for this research is that the proposed biological mechanism opens the way for pharmacological interventions, targeting kynurenine pathway enzymes, as well as for the development of biomarkers for peripartum depression and suicidality. In this proposal, levels and activity of the key kynurenine pathway enzyme and its downstream metabolites will be determined in placenta, blood, and monocytes from women during pregnancy and in the post-partum. Participants will be enrolled from a community-based population attending an ob/gyn clinic, as well as from a unique clinical program specializing in the treatment of suicidal women and their infants in the post-partum period, both in Grand Rapids, MI. Placentas will be collected at delivery. All study participants will be carefully diagnosed and assessed for psychiatric symptoms of depression and suicidality as well as risk-factors. Monocytes and placental trophoblasts will be cultured and the supernatant- and blood levels will be analyzed for kynurenine metabolites using Gas-Chromatography Mass-Spectrometry. The results will be validated in two co-horts of biobanked plasma and placenta tissue, respectively, from separate geographical locations. This study will determine whether peripartum depression is a distinct subtype of depression, with a pathophysiology similar to cytokine-induced depression. The findings can lead to the identification of new therapeutic targets and biomarkers for peripartum depression and suicidality.