Genome wide screening of transmembrane accessory subunits of ion channels

离子通道跨膜辅助亚基的全基因组筛选

• 批准号: 7938595
• 负责人: Susumu Tomita
• 金额: $ 50万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938595
• 关键词: Address; Affect; Agonist; Area; Behavior; Biological Assay; Brain; Catalytic Domain; Cell Line; Cells; Cloning; Cultured Cells; Detergents; Development; Disease; Drug Delivery Systems; Electrodes; Exhibits; Gastrointestinal tract structure; Gated Ion Channel; Genes; Genomics; Heart; Homeostasis; Human; Human Genome; Image; Individual; Injection of therapeutic agent; Integral Membrane Protein; Ion Channel; Ions; Kidney; Knowledge; Length; Ligands; Maintenance; Measures; Membrane; Membrane Potentials; Mental disorders; Methods; Molecular; Monitor; Myocardium; Neurologic; Neurosciences; Oocytes; Open Reading Frames; Organ; Performance; Pharmacology; Play; Property; Proteins; Proteomics; Pump; Recombinants; Regulation; Reporting; Research; Research Personnel; Role; Screening procedure; Signal Transduction; Surface; System; Systems Analysis; Technology; Time; Tissues; Validation; Work; Xenopus laevis; body system; expression cloning; extracellular; genome wide association study; genome-wide; innovation; luminescence; mind control; neural circuit; novel; novel strategies; overexpression; patch clamp; protein complex; protein expression; public health relevance; receptor; release of sequestered calcium ion into cytoplasm; stem; tool; trafficking; voltage clamp

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area 06: Enabling technologies and specific Challenge Topic Breakthrough technologies for neuroscience (06-NS-103). The title of this proposal is "Genomewide screening of transmembrane accessory subunits of ion channels". Ion homeostasis in organs (e.g., brain, heart, kidney, gastrointestinal tract, etc.) plays critical roles in human and its dysregulation causes lethality or serious disorders. Ion homeostasis is controlled by ion regulators, which include ion channels, transporters, and pumps. Because these proteins may represent drug targets to treat disease and disorders, extensive work has been carried out using genomic approaches to identify pore-forming or catalytic subunits of ion regulators at the molecular level via expression cloning using activity or homology searches. Cloned pore-forming channel subunits overexpressed in heterologous cells exhibit channel activity. However, differences in channel properties observed between recombinant and native channels have been reported for many channels, which were explained by the identification of accessory subunits recently (Jackson and Nicoll, 2009; Tigaret and Choquet, 2009). The existence of accessory subunits severely complicates the study of ion regulators, as the properties and pharmacology of ion regulators with accessory subunits are different. Furthermore, identification of novel accessory subunits burdens researchers with the cumbersome and time-consuming task of characterizing ion regulators by expressing pore-forming or catalytic subunits alone in heterologous cells. To overcome this limitation in the study of ion regulators, we would like to propose a systematic and genome wide screening method to identify transmembrane regulators/accessory subunits of ion channels. Because the human genome encodes more than 1,500 ion regulators, we believe that the successful development of the proposed screening method will impact a broad field of research pertaining to various organ systems and diseases caused by the dysregulation of ion homeostasis. Furthermore, this innovative approach to identify channel accessory subunits provides a new tool to understand the functioning and regulation of ion channels. Because alterations in many ion channels cause human disorders, which are termed channelopathies, we may identify new drug targets for these diseases. Furthermore, channelopathies affect not only the brain but also other tissues, which include the kidney, muscle, and heart. Therefore, the establishment of this approach will impact and stimulate a broad area of research pertaining to ion regulators. PUBLIC HEALTH RELEVANCE: We here propose a simple, but novel, approach to identify novel channel subunits systematically using a genome-wide screening approach. Because alterations in many ion channels cause human disorders, which are termed channelopathies, we may identify new drug targets for these diseases. Furthermore, channelopathies affect not only the brain but also other tissues, which include the kidney, muscle, and heart.

描述（由申请人提供）：此申请地址为广泛的挑战区域06：启用技术和特定的挑战主题突破性神经科学技术（06-NS-103）。该提案的标题是“对离子通道的跨膜附件亚基的全基因组筛选”。器官中的离子体内平衡（例如大脑，心脏，肾脏，胃肠道等）在人类及其功能障碍中起关键作用会引起致命性或严重的疾病。离子稳态由离子调节剂控制，其中包括离子通道，转运蛋白和泵。由于这些蛋白质可能代表治疗疾病和疾病的药物靶标，因此已经使用基因组方法进行了广泛的工作，以通过使用活动或同源性搜索来鉴定分子水平上离子调节剂的孔形成或催化亚基。在异源细胞中过表达的克隆孔形通道亚基表现出通道活性。然而，已经报道了许多通道的重组和天然通道之间观察到的通道性质差异，这是通过最近识别辅助亚基的识别来解释的（Jackson和Nicoll，2009； Tigaret和Choquet，2009）。附件亚基的存在严重复杂化了离子调节剂的研究，因为带有附件亚基的离子调节剂的性质和药理学不同。此外，通过在异源细胞中单独表达毛孔形成或催化亚基来表征离子调节剂的繁琐且耗时的任务，对研究人员的识别负担为研究人员负担负担。为了克服离子调节剂研究中的这一限制，我们想提出一种系统的和基因组宽筛选方法，以识别离子通道的跨膜调节剂/附件亚基。由于人类基因组编码超过1,500个离子调节剂，因此我们认为，提出的筛查方法的成功发展将影响与因离子稳态失调引起的各种器官系统和疾病有关的广泛研究领域。此外，这种识别通道附件亚基的创新方法为了解离子通道的功能和调节提供了一种新工具。由于许多离子通道的改变会导致人类疾病，这些疾病称为通道病，我们可能会确定这些疾病的新药物靶标。此外，通道病不仅会影响大脑，还影响其他组织，包括肾脏，肌肉和心脏。因此，这种方法的建立将影响并刺激与离子调节剂有关的广泛研究领域。 公共卫生相关性：我们在这里提出了一种使用全基因组筛查方法系统地识别新型渠道亚基的简单但新颖的方法。由于许多离子通道的改变会导致人类疾病，这些疾病称为通道病，我们可能会确定这些疾病的新药物靶标。此外，通道病不仅会影响大脑，还影响其他组织，包括肾脏，肌肉和心脏。