Calcium Sensing Proteins in Depression

描述（由申请人提供）：突触和结构可塑性改变在重度抑郁症（MDD）的发病机制中起着至关重要的作用;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。Ca 2+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Ca 2+稳态和Ca 2+信号转导发生改变。Ca 2+的不同作用是通过Ca 2+感应蛋白介导的;一个高度表征的成员是钙调素（CaM）。最近，已经鉴定了两个不同的Ca 2+感应蛋白亚家族，即，神经元Ca 2+感应（NCS）和钙结合（CaBP）蛋白，其在神经元中单独或高度表达。这些蛋白质以非常高的亲和力与Ca 2+结合，经历肉豆蔻酰化和构象变化，从而与特定靶蛋白相互作用以介导神经元功能。这些Ca 2+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极大兴趣的焦点。在一项初步研究中，我们发现，钙离子传感蛋白的表达不仅受到差异调节，但它们与特定的靶蛋白的相互作用也受到干扰，在MDD受试者的大脑。这些变化是非常具体的，因为在其他精神障碍中发现了相反的变化或没有变化，双相情感障碍（BPD）或精神分裂症（SCHIZ）。我们假设，Ca 2+传感蛋白，通过其以不同的方式改变表达，将影响它们与特定靶蛋白的相互作用，这将导致神经网络/通路的调制，涉及神经可塑性;这些改变将有助于MDD的发病机制。为了测试这一点，我们提出了一系列的实验研究Ca 2+传感及其特定的靶蛋白在分子和细胞水平上，在良好的特征和匹配的大脑样本从MDD和非精神正常对照组。我们将通过确定BPD或SCHIZ受试者大脑中的拟议措施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中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疾病有关的大脑区域进行，即PFC和海马体。更具体地，我们将检查：1）a）NCS蛋白NCS-1、VILIP 1、VILIP 2、VILIP 3、钙调蛋白、神经钙蛋白4和DREAM; B）CaBP蛋白CaBP 1和CaBP 4;和c）钙调蛋白的表达和/或功能特征; 2）这些Ca 2+感应蛋白与特定靶点的相互作用，即，PI 4-激酶2、三磷酸肌醇受体、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导致我们对MDD相关分子机制的理解取得根本性突破，并为MDD治疗的新型靶向药物发现提供关键的新见解。公共卫生相关性：我们提出的研究将产生有关抑郁症神经生物学的重要信息，并可能为治疗干预提供可能的新位点，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.