BDNF-Trk Signaling & Cytokines in Patients with Mood Disorders

描述(由申请人提供)：在我们先前资助的基金中，我们研究了PI和Wnt信号通路在情绪障碍(MD)患者中的作用。我们发现自杀患者和MD患者的血小板5HT2A受体增加，双相情感障碍患者的PKC同工酶和活性降低，MD患者的血小板和淋巴细胞中BDNF的蛋白和mRNA表达显著降低。其中一些发现需要进一步研究，特别是这些患者BDNF降低的生理意义。在之前的资助期间，我们收集了40名特征良好的无药物的重度抑郁障碍(MDD)患者、40名双相躁狂或混合型(BPM)患者、40名正常对照受试者和19名双相抑郁(BPD)患者的血小板、淋巴细胞、中性粒细胞和血浆。我们现在建议主要研究这些患者BDNF减少的生理后果和原因。BDNF的生理作用主要由PLC、MAP激酶和PI3-激酶途径介导。抑郁症患者的HPA功能异常是生物精神病学中最一致的发现之一。另一方面，HPA的功能也受到炎性细胞因子的调节。简而言之，我们建议的研究的具体目标如下。具体目的1.检测非药物依赖的MD患者中性粒细胞中ERK-1、ERK-2、MEK-1、MEK-2和RAS的蛋白和mRNA表达。具体目的2.我们将测定MD患者血小板中PI-3-K途径各组成部分的蛋白和mRNA的表达，包括PI-3-K亚基和Akt异构体。具体目的3.检测MD患者中性粒细胞和淋巴细胞中糖皮质激素受体GR和MR以及转录因子GRE和NF：B的蛋白和mRNA表达。具体目的4.检测MD患者血浆中促炎症细胞因子IL-12、IL-6、肿瘤坏死因子1、CD40-L和组织因子的水平。具体目标5.我们将检查任何拟议措施中的异常是否为状态标记或特征标记。具体目的6.我们将检验所提出的标记物与地塞米松抑制试验(DST)的关系。这些研究将检验一种假设，即在MD中观察到的BDNF减少的功能后果与通过MAP激酶和PI 3-激酶通路的BDNF信号改变有关；而在抑郁症中观察到的HPA功能异常与糖皮质激素受体改变引起的反馈机制改变有关。情绪障碍是一个主要的公共卫生问题，不仅需要更好地了解MD的病理生理学，而且还需要更好地了解其潜在的细胞和分子机制。这项拟议的研究不仅将加强我们对与MD相关的生物异常的了解，还可能导致识别抑郁症和双相情感疾病的潜在有用生物标记物，并发现更合适的位置，以开发更好的抑郁症和双相情感疾病治疗药物。 公共卫生相关性：情绪障碍(MD)是一个主要的公共卫生问题。与这些疾病相关的病理生理异常尚不清楚，但推测它们可能与单胺受体及其第二信使的异常有关。MD患者存在脑源性神经营养因子和HPA轴的异常。本研究将探讨脑源性神经营养因子介导的HPA功能障碍的信号转导途径和机制。

DESCRIPTION (provided by applicant): In our previously funded grant we studied the roles of the PI and the Wnt signaling pathways in patients with mood disorders (MD). We found that 5HT2A receptors were increased in the platelets of suicidal patients and patients with MD, PKC isozymes and activity were decreased in patients with bipolar illness, and protein and mRNA expression of BDNF was significantly decreased in the platelets and lymphocytes of patients with MD. Some of these findings need further investigation, especially the physiological significance of decreased BDNF in these patients. During the previous funding period we collected platelets, lymphocytes, neutrophils, and plasma from 40 well-characterized drug-free patients with major depressive disorder (MDD), 40 bipolar manic or mixed (BPM), 40 normal control subjects and from 19 bipolar depressed (BPD) patients. We now propose to study primarily the physiological consequences and the reasons for decreased BDNF in these patients. The physiological effects of BDNF are primarily mediated by PLC, the MAP kinase, and the PI 3-kinase pathways. An abnormal HPA function in depression is one of the most consistent findings in biological psychiatry. HPA function, on the other hand, is also regulated by inflammatory cytokines. Briefly, the specific aims of our proposed studies are as follows. Specific Aim 1. We will determine the protein and mRNA expression of ERK-1, ERK-2, MEK-1, MEK-2, and Ras in the neutrophils of drug-free patients with MD. Specific Aim 2. We will determine the protein and mRNA expression of components of the PI 3-kinase pathway, including PI 3-kinase subunits, and Akt isoforms in the platelets of patients with MD. Specific Aim 3. We will determine the protein and mRNA expression of the glucocorticoid receptors GR and MR and the transcription factors GRE and NF:B in the neutrophils and lymphocytes of patients with MD. Specific Aim 4. We will determine the levels of pro-inflammatory cytokines, namely, IL-12, IL-6, TNF1, CD 40-L and tissue factor, in the plasma of patients with MD. Specific Aim 5. We will examine if the abnormalities in any of the proposed measures are state or trait markers. Specific Aim 6. We will examine the relationship of the proposed markers to dexamethasone suppression test (DST).These studies will test the hypothesis that the functional consequences of the observed decrease in BDNF in MD are related to altered BDNF signaling through the MAP kinase and the PI 3-kinase pathways; and the observed abnormalities of HPA function in depression are related to changes in the feedback mechanism due to alterations of glucocorticoid receptors. Mood disorders are a major public health concern and there is a need for a better understanding not only of the pathophysiology of MD but also the underlying cellular and molecular mechanisms. The proposed research will not only enhance our understanding of the biological abnormalities associated with MD, but may also result in the identification of potentially useful biomarkers for depression and bipolar illness and the detection of more appropriate sites for developing better therapeutic agents for depression and bipolar illness. PUBLIC HEALTH RELEVANCE: The mood disorders (MD) are a major public health concern. The pathophysiological abnormalities associated with these disorders are unclear but it is hypothesized that they may be related to abnormalities in monoamine receptors and their second messengers. Abnormalities of BDNF and HPA axis have been observed in patients with MD. This research will investigate BDNF-mediated signaling pathways and mechanisms of HPA dysfunction.