Single nucleotide polymorphisms of neuronal CACNA1C L-type calcium channels assoc

神经元CACNA1C L型钙通道关联的单核苷酸多态性

基本信息

批准号：
7785050
负责人：
Diane Lipscombe
金额：
$ 24.26万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7785050
关键词：
Adult Adverse effects Affect Alternative Splicing Ankyrins Architecture Attention Behavior Behavioral Binding Binding Sites Bipolar Disorder Brain Brain imaging Brain region Calcium Calcium Channel Calcium Channel Blockers Cardiac Cell Death Cell Nucleus Cell physiology Cells Chromosomes, Human, Pair 12 Chronic Comorbidity Data Development Disease Drug Delivery Systems Embryo Event Exons Funding Mechanisms Gene Combinations Gene Expression Genes Heart Diseases Hereditary Disease Hippocampus (Brain)Human Human Chromosomes Hypertension Individual Introns Knockout Mice L-Type Calcium Channels Link Lithium Manic Maps Mental Depression Mental disorders Molecular Mus Muscle Contraction Mutation Neurons Nucleotides Patients Pattern Population Study Positioning Attribute Predisposition RNA RNA Splicing RNA-Binding Proteins Reading Regulatory Element Risk Risk Factors Role Safety Second Messenger Systems Signal Transduction Single Nucleotide Polymorphism Single Nucleotide Polymorphism Map Site Staging Structure Surface Synapses System Testing Time Timothy syndrome Translations United States Variant Work base common treatment density disorder control genome wide association study high risk insight interest mRNA Precursor nervous system disorder neuronal growth neurotransmitter release novel painful neuropathy postsynaptic protein expression public health relevance second messenger theories voltage

项目摘要

DESCRIPTION (provided by applicant): This is a new R21 application to study the role of a neuronal calcium channel in determining susceptibility to bipolar disorder. All excitable cells use calcium ion channels on their surface to read electrical signals and convert them into a change in intracellular calcium, a ubiquitous second messenger. Calcium controls a huge number of cellular processes including muscle contraction, neurotransmitter release, cell death and neuronal growth. Calcium ion channels are important drug targets for treating hypertension and neuropathic pain. Mutations in the CACNA1C calcium ion channel gene cause a rare hereditary disorder Timothy Syndrome and single nucleotide polymorphisms identified very recently in the same CACNA1C gene associate with bipolar disorder. Bipolar disorder is a chronic mental illness affecting close to 6 million adults in the United States characterized by cyclical episodes of mania and depression. The most common treatment is lithium but this agent is only partially effective, has numerous side effects, and a low safety margin. There is a clear inheritable risk in bipolar disorder. Recently a large, collaborative genome-wide association study analyzed >10,000 bipolar and control individuals and identified a region in human chromosome 12 that has significant association with bipolar disorder. Bipolar disease-associated single nucleotide polymorphisms mapped to a long intron in an uncharacterized region of the CACNA1C gene. This exciting discovery affords us a unique opportunity to understand how single nucleotide variations in the CACNA1C gene could disrupt normal calcium channel activity in the brain. We will use a combination of gene and RNA analyses, and electrophysiological recordings to explore how this potential site of bipolar susceptibility in CACNA1C controls calcium ion channel function. Our work has the potential to provide novel insights into the molecular mechanisms underlying bipolar disorder. ) PUBLIC HEALTH RELEVANCE: This R21 project will test the hypothesis that a long intron in the CACNA1C gene, recently identified as a risk factor in bipolar disorder, controls calcium channel function through alternative pre-mRNA splicing. We will use a combination of RNA, gene, and electrophysiological analyses to reveal the functional role of intron 4 in controlling L-type calcium channel activity in neurons.

描述（由申请人提供）：这是研究神经元通道在确定对躁郁症易感性方面的作用的新R21应用。所有可激发的细胞在其表面上使用钙离子通道来读取电信号，并将其转化为细胞内钙的变化，这是无处不在的第二信使。钙控制大量细胞过程，包括肌肉收缩，神经递质释放，细胞死亡和神经元生长。钙离子通道是治疗高血压和神经性疼痛的重要药物靶标。 CACNA1C钙离子通道基因的突变引起罕见的遗传疾病蒂莫西综合征和单核苷酸多态性，最近在同一CACNA1C基因与双相情感障碍的同一基因中鉴定出来。双相情感障碍是一种慢性精神疾病，影响了美国的近600万成年人，其特征是躁狂和抑郁症的周期性发作。最常见的治疗方法是锂，但该药物仅部分有效，具有许多副作用和较低的安全边缘。躁郁症有明显的遗传风险。最近，一项大型，合作的全基因组协会研究分析了> 10,000个双极性和对照个体，并确定了人类染色体中与双相情感障碍有显着关联的区域。双极疾病相关的单核苷酸多态性映射到CACNA1C基因的未表征区域中的长内含子。这一令人兴奋的发现为我们提供了一个独特的机会，可以理解CACNA1C基因中的单个核苷酸变化如何破坏大脑中正常的钙通道活性。我们将使用基因和RNA分析以及电生理记录的组合来探讨CACNA1C中双极易感性的潜在位点如何控制钙离子通道功能。我们的工作有可能提供对双相情感障碍基础机制的新见解。）公共卫生相关性：这个R21项目将检验以下假设：CACNA1C基因中的较长内含子（最近被确定为躁郁症的危险因素）通过替代性mRNA剪接来控制钙通道功能。我们将使用RNA，基因和电生理分析的组合来揭示内含子4在控制神经元中L型钙通道活性中的功能作用。