Development of High-expressing Ion Channels for Research and Therapeutic Applicat

用于研究和治疗应用的高表达离子通道的开发

• 批准号: 8775955
• 负责人: JOSEPH Benjamin RUCKER
• 金额: $ 26.4万
• 依托单位: INTEGRAL MOLECULAR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775955
• 关键词: Abbreviations; Affect; American; Animals; Antibodies; Autoimmunity; Bacteriophages; Binding; Biochemical; Biological Assay; Biological Products; Biomedical Research; Chimera organism; Clinical; Clinical Trials; Development; Disease; Engineering; FDA approved; Family member; Flow Cytometry; Gated Ion Channel; Goals; Health; Human; Immune System Diseases; Immunization; Immunofluorescence Immunologic; Industry; Ion Channel; Ion Channel Protein; Libraries; Literature; Measures; Membrane Proteins; Monoclonal Antibodies; Pain; Phage Display; Pharmacologic Substance; Potassium; Property; Protons; Reagent; Research; Sodium; Specificity; Structure; Surface; Technology; Testing; Therapeutic; Therapeutic Human Experimentation; Therapeutic Monoclonal Antibodies; Time; Toxic effect; Toxin; Variant; Virus-like particle; Western Blotting; base; design; high throughput screening; human disease; interest; novel; patch clamp; protein expression; public health relevance; scaffold; sensor; small molecule; success; voltage

DESCRIPTION (provided by applicant): Ion channels, such as Kv1.3 and Nav1.7, are involved in a number of human disorders, including autoimmunity and pain that affect >100 million Americans annually and are poorly treated. However, ion channels are typically exceptionally difficult to express at high levels due to their structural complexity and toxicity. s a result, many research and therapeutic applications for these targets have been very limited where high-levels of membrane protein are required. For example, for human voltage-gated potassium (Kv) and sodium (Nav) ion channels, there are no solved crystal structures and no therapeutic monoclonal antibodies (MAbs) approved by the FDA or even in clinical trials, despite the high level of pharmaceutical interest in such MAbs as therapeutics. These applications all typically require high levels of protein expression, and the expression of most ion channels is usually orders of magnitude below what is required for success. Here we propose to develop a versatile platform for expressing high levels of conformational ion channel proteins. Our use of this platform within the scope of this proposal will be for isolating unique MAbs against Kv1.3 and Nav1.7. We expect that this platform will be extensible to other ion channels and will also have utility for structural research, high-throughput screening, and as biomedical research reagents.

描述（由申请人提供）：离子通道，如Kv1.3和Nav1.7，参与许多人类疾病，包括自身免疫和疼痛，每年影响超过1亿美国人，治疗效果不佳。然而，由于其结构复杂性和毒性，离子通道通常非常难以高水平表达。因此，在需要高水平膜蛋白的情况下，这些靶点的许多研究和治疗应用非常有限。例如，对于人电压门控钾（Kv）和钠（Nav）离子通道，没有溶解的晶体结构，也没有FDA批准的治疗性单克隆抗体（MAb），甚至在临床试验中，尽管这种MAb作为治疗剂具有高水平的药学兴趣。这些应用通常都需要高水平的蛋白质表达，并且大多数离子通道的表达通常低于成功所需的数量级。在这里，我们建议开发一个通用的平台，表达高水平的构象离子通道蛋白。我们在本提案范围内使用该平台将用于分离针对Kv1.3和Nav1.7的独特MAb。我们希望这个平台将可扩展到其他离子通道，也将具有实用性的结构研究，高通量筛选，并作为生物医学研究试剂。