PKC Substrates & Transcription Factors in Mood Disorders

描述(由申请人提供)：在了解与抑郁症和双相情感障碍相关的神经生物学异常方面取得了重大进展。然而，这些疾病中这种异常的具体部位仍不清楚。多项研究表明，情绪障碍患者大脑和血小板中5HT2A受体和5HT2A受体相关的磷脂酰肌醇(PI)信号活性增加。前期研究表明，单相患者血小板5HT2A受体和IP3受体增加，双相患者血小板PKC活性、PLC活性和PKC、PLC选择性同工酶活性降低，PKC底物Marcks增加。在拟议的研究中，主要目的是扩展我们的发现，并进一步研究PI信号系统中的下游事件，例如：非药物单相和双相患者获得的血小板和中性粒细胞中的PKC底物和转录因子。 更具体地说，我们将研究PKC的底物PKC、MARKCS和GAP43在单相和双相患者的血小板中的转录因子AP-1、GRE的DNA结合活性、另一种转录因子CREB的DNA结合活性、蛋白表达和mRNA水平。此外，我们还将研究GSK-3B和B-连环蛋白的活性、蛋白水平和mRNA水平，这是WNT通路的两个重要组成部分，似乎与PKC有关，并可能受PKC调节，已被认为在双相情感障碍中异常。我们提出的研究基于我们的中心假设，即情绪障碍患者的PT信号系统异常与其几个组成部分的异常相关，导致转录因子和基因表达异常。这些研究将加深我们对转录因子和PKC底物在单相和双相情感障碍病理生理中的参与的理解，并可能表明它们是否可能是抗抑郁药物和情绪稳定药物治疗作用的可能部位，从而可能导致更合适和更好的治疗这些疾病。

DESCRIPTION (provided by applicant): Significant progress has been made in the understanding of the neurobiological abnormalities associated with depression and bipolar disorders. However, the specific sites of such abnormalities in these disorders are still unclear. Several studies indicate increased 5HT2A receptors and 5HT2A receptor linked phosphoinositide (PI) signaling activity in the brain and platelets of patients with mood disorder. The studies in the previous funding period, indicated that 5HT2A receptors and IP3 receptors are increased in the platelets of unipolar patients, PKC activity, PLC activity and selective isozymes of PKC and PLC are decreased and MARCKS, a substrate for PKC increased in the platelets of bipolar patients. In the proposed research, the main objective is to extend our findings and to study further downstream events in the PI signaling system, such as: PKC substrates and transcription factors in the platelets and neutrophils obtained in drug-free unipolar and bipolar patients. More specifically, we will study PKC, MARKCS and GAP43 the substrates for PKC, in the platelets of unipolar and bipolar patients, DNA binding activity of transcription factors AP-1, GRE, DNA binding activity, protein expression and mRNA levels of another transcription factor CREB in the neutrophils of unipolar and bipolar patients. In addition, we will study the activity, protein level and mRNA levels of GSK-3B and protein levels of B-catenin, the two important components of the WNT pathway that appears to be related to and may be regulated by PKC and has been implicated to be abnormal in bipolar disorders. Our proposed studies are based on our central hypothesis that an abnormal PT signaling system in patients with mood disorders is associated with abnormality of several of its components leading to abnormality of transcription factors and gene expression.These studies will enhance our understanding of the involvement of transcription factors and PKC substrates in the pathophysiology of unipolar and bipolar disorders and may indicate if they may be possible sites for therapeutic action of antidepressants and mood stabilizing drugs, thus, may result in more appropriate and better treatment these disorders.