Role of Kynurenine Pathway Metabolites in Perinatal Depression and Suicidality

犬尿氨酸途径代谢物在围产期抑郁和自杀中的作用

• 批准号: 8766242
• 负责人: Lena Cecilia Brundin
• 金额: $ 40.11万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766242
• 关键词: Address; Affect; Agonist; Biochemical Reaction; Biological; Biological Markers; Biological Process; Blood; Brain; Carboxy-Lyases; Cerebrospinal Fluid; Cessation of life; Clinic; Clinical; Communities; Coupled; Data; Depressed mood; Depression and Suicide; Development; Diagnosis; Enrollment; Enzymes; Exhibits; Feeling suicidal; Fetus; Figs - dietary; First Pregnancy Trimester; Functional disorder; Geographic Locations; Glutamates; Goals; Individual; Infant; Inflammation; Intervention; Knowledge; Kynurenine; Lead; Mass Fragmentography; Measurable; Measures; Mental Depression; Mission; Modeling; Mood Disorders; Mothers; N-Methyl-D-Aspartate Receptors; National Institute of Child Health and Human Development; National Institute of Mental Health; Neurons; Outcome; Participant; Pathway interactions; Patients; Perinatal; Picolinic Acids; Placenta; Plasma; Postpartum Depression; Pregnancy; Pregnant Women; Prevention; Property; Publishing; Quinolinic Acid; Research; Risk; Risk Factors; Role; Stream; Suicide; Symptoms; Testing; Tissues; Tryptophan; Vulnerable Populations; Woman; Work; biobank; critical period; cytokine; depressive symptoms; enzyme pathway; improved; indole-2,3-dioxygenase; monocyte; neurochemistry; neuroinflammation; neurotoxic; neurotransmission; new therapeutic target; novel therapeutics; peripheral blood; population based; programs; public health relevance; response; screening; suicidal; suicidal patient; suicidal women; tool; trophoblast

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.

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，本建议的目标是确定导致围产期抑郁症的生物学过程，并找到可测量的结果，用于确定谁有患围产期抑郁症的风险。核心假设是，缺乏犬尿氨酸途径中一种关键酶活性的女性在怀孕后会出现抑郁和自杀倾向。在怀孕期间，胎盘中的犬尿氨酸途径会分解色氨酸，将代谢物释放到血液中，这些代谢物会影响谷氨酸神经传递，进而对大脑产生影响。这一假设来源于强有力的初步数据，这些数据表明，有自杀念头的抑郁症患者