PKC Substrates & Transcription Factors in Mood Disorders

描述（由申请人提供）：在理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，情绪障碍患者的大脑和血小板中5HT2A受体和5HT2A受体相关磷酸肌苷（PI）信号活性增加。前期资助期的研究表明，单极患者血小板中5HT2A受体和IP3受体升高，PKC活性、PLC活性和PKC和PLC的选择性同工酶降低，双相患者血小板中PKC底物MARCKS升高。在这项研究中，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：在无药单极和双相患者中获得的血小板和中性粒细胞中的PKC底物和转录因子。

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.