Calcium Sensing Proteins in Depression

描述（由申请人提供）：突触和结构可塑性的改变在重度抑郁症（MDD）的发病机制中起关键作用；然而，导致这种可塑性改变的事件的精确分子和细胞性质仍不清楚。Ca2+是在突触和结构可塑性的启动和调节中起决定性作用的关键分子之一。相当多的证据表明，改变Ca2+稳态和Ca2+信号在MDD。Ca2+的各种作用是通过Ca2+传感蛋白介导的；一个高度表征的成员是钙调蛋白（CaM）。最近，已经鉴定出两个不同的Ca2+传感蛋白亚家族，即神经元Ca2+传感（NCS）和钙结合（CaBP）蛋白，它们在神经元中单独或高度表达。这些蛋白以非常高的亲和力与Ca2+结合，经历肉豆蔻酰化和构象变化，从而与特定的靶蛋白相互作用，介导神经元功能。这些Ca2+传感/结合蛋白及其新的靶蛋白作为可塑性现象的潜在分子开关已成为人们关注的焦点。在一项初步研究中，我们发现在MDD受试者的大脑中，Ca2+传感蛋白的表达不仅受到差异调节，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，要么没有发现变化。我们假设Ca2+传感蛋白，通过其以独特的方式改变表达，将影响它们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的发病机制。为了验证这一点，我们提出了一系列的实验，在分子和细胞水平上检查Ca2+传感及其特定的靶蛋白，在从重度抑郁症和非精神正常对照受试者中获得的具有良好特征和良好匹配的脑样本中。我们将通过确定BPD或SCHIZ受试者大脑的拟议测量来检查这些变化的特异性。此外，我们将通过检查从不同队列获得的脑样本来确定重度抑郁症变化的一致性。这些研究将在涉及情感性疾病的两个大脑区域进行，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、hippocalcin、neurocalcin 4和DREAM的表达和/或功能特征；b) CaBP蛋白CaBP1和CaBP4；c)钙调素；2)这些Ca2+传感蛋白与特定靶点的相互作用，即PI 4-激酶2、肌醇三磷酸受体、CREB、神经元凋亡抑制蛋白、CaM激酶II、CaM激酶IV和钙调磷酸酶；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导致我们对重度抑郁症相关分子机制的理解取得根本性突破，并为新型靶向药物治疗重度抑郁症提供重要的新见解。公共卫生相关性：我们提出的研究将为抑郁症的神经生物学提供重要信息，并可能为治疗干预提供可能的新途径，最终可能导致更好的治疗和预防抑郁症。

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. PUBLIC HEALTH RELEVANCE: Our proposed study will yield important information on the neurobiology of depression and may indicate possible novel sites for therapeutic interventions, which may eventually lead to better treatment and possibly prevention of depression.