Calcium Sensing Proteins in Depression

抑郁症中的钙敏感蛋白

• 批准号: 7900955
• 负责人: Yogesh Dwivedi
• 金额: $ 27.48万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900955
• 关键词: 1-Phosphatidylinositol 4-Kinase; Address; Affect; Affective; Affinity; Antibodies; Apoptotic; Area; Autopsy; Baculoviruses; Binding; Binding Proteins; Biological Assay; Biological Neural Networks; Bipolar Disorder; Brain; CREB1 gene; Ca(2+)-Calmodulin Dependent Protein Kinase; CabP1; Calcineurin; Calcium; Calcium Binding; Calmodulin; Calmodulin-Binding Proteins; Characteristics; Clinical Research; Co-Immunoprecipitations; Cytosol; DNA Binding; Egtazic Acid; Electrophoretic Mobility Shift Assay; Event; Family; Hand; Hippocampus (Brain); Homeostasis; ITPR1 gene; Immunohistochemistry; Immunoprecipitation; Inositol; Lead; Major Depressive Disorder; Measures; Mediating; Membrane; Mental Depression; Mental disorders; Messenger RNA; Molecular; Nature; Neurobiology; Neuronal Plasticity; Neurons; Nuclear; Nuclear RNA; Pathogenesis; Pathway interactions; Phosphatidylinositols; Play; Population; Prevention; Protein Binding; Proteins; RNA; Regulation; Research Design; Role; Sampling; Schizophrenia; Series; Signal Transduction; Site; Specificity; Statistical Models; Suicide; Synapses; Synaptic Membranes; Synaptic Vesicles; Testing; Therapeutic Intervention; Time; Transcription Repressor/Corepressor; VSNL1 gene; Western Blotting; base; calmodulin-dependent protein kinase II; calsenilin; cohort; design; drug discovery; hippocalcin; inorganic phosphate; insight; interest; member; myristoylation; neuron apoptosis; novel; pre-clinical; prevent; protein expression; public health relevance; receptor; research study; selective expression

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.

描述（由申请人提供）：突触和结构可塑性改变在主要抑郁症的发病机理（MDD）中起着至关重要的作用；但是，导致这种可塑性改变的事件的精确分子和细胞性质尚不清楚。 Ca2+是在启动和调节突触可塑性中起决定性作用的关键分子之一。大量证据表明，MDD中的Ca2+稳态和Ca2+信号传导改变了。 Ca2+的各种作用是通过Ca2+传感蛋白介导的。一个高度特征的成员是钙调蛋白（CAM）。最近，已经鉴定出了Ca2+感应蛋白的两种不同的亚家族，即神经元Ca2+传感（NCS）和钙结合（CABP）蛋白，它们仅在神经元中或高度表达。这些蛋白质具有非常高的亲和力与Ca2+结合，经历肉豆蔻酰化和构象变化，从而与特定靶蛋白相互作用以介导神经元功能。这些Ca2+感应/结合蛋白及其新型靶蛋白已成为塑性现象的潜在分子开关的重点。在一项初步研究中，我们发现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在MDD受试者的大脑中也受到干扰。这些变化非常具体，因为其他精神障碍，即双相情感障碍（BPD）或精神分裂症（Schiz），发现相反或没有变化。我们假设Ca2+传感蛋白通过其不同的表达方式会影响其与特定靶蛋白的相互作用，这将导致神经网络/途径的调节，与神经可塑性有关。这些改变将有助于MDD的发病机理。为了测试这一点，我们提出了一系列实验，以在分子和细胞水平上检查Ca2+传感及其特异性靶蛋白，以及从MDD和非精神病患者获得的良好特征和匹配良好的脑样品中。我们将通过确定BPD或Schiz受试者的大脑中提出的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。这些研究将在两个大脑区域进行，涉及情感疾病，即PFC和海马。更具体地说，我们将研究：1）A）NCS蛋白NCS-1，Vilip1，Vilip2，Vilip3，Vilip3，Hippocalcin，Hippocalcin，Neurocalcin 4和Dream的表达和/或功能特征； b）CABP蛋白CABP1和CABP4； c）钙调蛋白； 2）这些Ca2+传感蛋白与特定靶标的相互作用，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和钙调蛋白； 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与MDD相关的分子机制的理解，并为新型基于目标的药物发现用于治疗MDD的新见解。公共卫生相关性：我们拟议的研究将产生有关抑郁症神经生物学的重要信息，并可能表明治疗性干预措施的新颖地点可能最终导致更好的治疗以及可能预防抑郁症。