Calcium Sensing Proteins in Depression

描述(申请人提供)：突触和结构可塑性改变在严重抑郁障碍(MDD)的发病机制中起着关键作用；然而，导致这种可塑性改变的事件的确切分子和细胞性质仍不清楚。钙离子是启动和调节突触和结构可塑性的关键分子之一。大量证据表明，MDD中的钙稳态和钙信号发生了改变。钙离子的不同作用是通过钙离子感应蛋白来实现的，钙调素(CaM)是其中一个具有高度特性的成员。近年来，发现了两个不同的钙敏感蛋白亚家族，即神经元钙敏感蛋白(NCS)和钙结合蛋白(CABP)，它们在神经元中单独或高表达。这些蛋白以很高的亲和力与钙离子结合，经历肉豆蔻化和构象变化，从而与特定的靶蛋白相互作用，介导神经元功能。这些钙离子感应/结合蛋白及其新的靶蛋白作为潜在的可塑性现象的分子开关已成为人们关注的焦点。在初步研究中，我们发现，在MDD受试者的大脑中，钙离子感应蛋白的表达不仅受到差异调控，而且它们与特定靶蛋白的相互作用也受到干扰。这些变化是非常具体的，因为在其他精神障碍，即双相情感障碍(BPD)或精神分裂症(SCHIZ)中，要么相反，要么没有变化。我们推测，钙敏感蛋白通过其不同方式的改变表达，将影响其与特定靶蛋白的相互作用，这将导致神经网络/通路的调节，涉及神经可塑性；这些改变将有助于MDD的发病。为了验证这一点，我们提出了一系列实验，在分子和细胞水平上检测钙离子感应及其特定的目标蛋白，这些样本来自MDD和非精神病学正常对照受试者，这些样本具有良好的特征和匹配。我们将通过在BPD或SCHIZ受试者的大脑中确定建议的措施来检验这些变化的特异性。此外，我们将通过检查从不同队列获得的大脑样本来确定MDD变化的一致性。这些研究将在两个与情感性疾病有关的大脑区域进行，即PFC和海马体。更具体地说，我们将研究：1)NCS蛋白NCS-1、VILIP1、VILIP2、VILIP3、HAMCALIN、Neurocalin 4和DREAM的表达和/或功能特征；b)CABP蛋白CaBP1和CaBP4；以及c)钙调蛋白；2)这些钙离子敏感蛋白与特定靶点的相互作用，即PI 4-Kin2、肌醇三磷酸受体、CREB、神经细胞凋亡抑制蛋白、CaM Kinase II、CaM Kinase IV和Calcineurin；3)这些靶蛋白的表达和/或功能特征。我们提出的研究可能会在我们对MDD相关分子机制的理解上取得根本性突破，并为MDD治疗的新靶点药物发现提供重要的新见解。

DESCRIPTION (provided by applicant): Altered synaptic and structural plasticity play a crucial role in the pathogenesis of major depressive disorder (MDD); however, the precise molecular and cellular nature of events that lead to such altered plasticity remains unclear. Ca2+ is one of the critical molecules that play a decisive role in initiating and regulating synaptic and structural plasticity. A considerable body of evidence points to altered Ca2+ homeostasis and Ca2+ signaling in MDD. The varied effects of Ca2+ are mediated through Ca2+ sensing proteins; one highly characterized member is calmodulin (CaM). Recently, two different subfamilies of Ca2+ sensing proteins have been identified, i.e., neuronal Ca2+ sensing (NCS) and calcium binding (CaBP) proteins, that are solely or highly expressed in neurons. These proteins bind to Ca2+ with a very high affinity, undergo myristoylation and conformational changes, and thereby, interact with specific target proteins to mediate neuronal functions. These Ca2+ sensing/binding proteins and their novel target proteins have become a focus of great interest as potential molecular switches for plasticity phenomena. In a preliminary study, we found that the expression of Ca2+ sensing proteins are not only differentially regulated, but their interaction with specific target proteins are also disturbed in brains of MDD subjects. These changes were quite specific as either opposite or no changes were found in other mental disorders, i.e., bipolar disorder (BPD) or schizophrenia (SCHIZ). We hypothesize that Ca2+ sensing proteins, via their altered expression in a distinct manner, will affect their interactions with specific target proteins, which will lead to modulation in neural network/pathways, implicated in neural plasticity; these alterations will contribute to the pathogenesis of MDD. To test this, we propose a series of experiments examining Ca2+ sensing and their specific target proteins at molecular and cellular levels, in well-characterized and well-matched brain samples obtained from MDD and nonpsychiatric normal control subjects. We will examine the specificity of these changes by determining the proposed measures in brains of BPD or SCHIZ subjects. In addition, we will determine the consistency of changes in MDD by examining brain samples obtained from a different cohort. These studies will be performed in two brain areas, implicated in affective illnesses, namely, PFC and hippocampus. More specifically, we will examine: 1) expression and/or functional characteristics of a) NCS proteins NCS-1, VILIP1, VILIP2, VILIP3, hippocalcin, neurocalcin 4, and DREAM; b) CaBP proteins CaBP1 and CaBP4; and c) calmodulin; 2) the interactions of these Ca2+ sensing proteins with specific targets, i.e., PI 4-kinase 2, inositol trisphosphate receptors, CREB, neuronal apoptotic inhibitory protein, CaM kinase II, CaM kinase IV, and calcineurin; 3) the expression and/or functional characteristics of these target proteins. Our proposed study could lead to a fundamental breakthrough in our understanding of the molecular mechanisms associated with MDD, and also provide critical new insight for novel target-based drug discoveries for the treatment of MDD.