Delayed Rectifier K Channel Biogenesis is Unveiled in Models of Long QT Syndrome

长 QT 综合征模型中揭示了延迟整流 K 通道生物发生

• 批准号: 7468128
• 负责人: Brian P Delisle
• 金额: $ 29.3万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468128
• 关键词: Action Potentials; Affect; Arrhythmia; Biochemical; Biogenesis; Cardiac; Cell surface; Cells; Complex; Data; Degradation Pathway; Depth; Disease; Endoplasmic Reticulum; Environment; Ethers; Ethyl Ether; Gene-Modified; Genes; Genetic; Genotype; Goals; Health; Heart; Heart Diseases; Human; Imaging Techniques; Inherited; Intracellular Transport; Link; Long QT Syndrome; Mammalian Cell; Membrane; Missense Mutation; Modeling; Molecular; Molecular Chaperones; Mutation; Numbers; Palpitations; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Potassium Channel; Property; Public Health; Purpose; Quality Control; Rare Diseases; Research; Seizures; Syncope; Syndrome; Testing; Therapeutic; Transport Vesicles; Voltage-Gated Potassium Channel; cytotoxic; intracellular protein transport; loss of function; novel; novel therapeutics; prevent; protein folding; protein misfolding; sudden cardiac death; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Every year, sudden cardiac death claims up to 25,000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being sought, and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. Most congenital LQT syndrome patients have mutations in either the KCNQ1 or KCNH2 (human ether a-go-go- related) genes, which encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that KCNQ1 (LQT1) mutations and KCNH2 (LQT2) mutations typically result in a loss of function. Many LQT1 and most LQT2 mutations cause Kv7.1 and Kv11.1 to be retained in Endoplasmic Reticulum (ER), thereby decreasing the number of functional channels expressed at the cell surface. Thus far, mechanisms that increase the ER export and functional expression have only been identified for trafficking deficient LQT2 mutations, and, unfortunately, most of these mechanisms do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations, we propose to study cellular properties that direct the ER retention for LQT1 and LQT2 mutations, and the ER export and trafficking for wild type (WT) Kv7.1 and Kv11.1. We will test that hypothesis: The ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control, and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that modulating interactions between chaperones, co-chaperones, and Kv7.1 or Kv11.1 will selectively increase the functional expression for different trafficking deficient LQT1 and LQT2 mutations, and that the vesicular transport properties for Kv7.1 and Kv11.1 can be manipulated to increase their functional expression. PUBLIC HEALTH RELEVANCE: Every year sudden cardiac death claims up to 25,000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being identified, and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. About one in 7,000 people have LQT1 or LQT2, which is caused by mutations in either the KCNQ1 or KCNH2 genes, respectively. These genes encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that LQT1 and LQT2 mutations typically result in a loss of function. The mechanisms that underlie the loss of function varies, but it is now recognized that many of these mutations decrease the number of functional channels expressed at the cell surface, because they are retained inside the cell in the Endoplasmic Reticulum (ER). Thus far, mechanisms that increase the functional expression for these mutations have only been identified for LQT2 and do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations, we propose to study the cellular quality control and vesicular transport properties for Kv7.1 and Kv11.1. We will test the hypothesis that the ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control, and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that we will identify novel ways to increase the functional expression for trafficking deficient LQT1 and LQT2 mutations.

描述（由申请人提供）：每年，多达 25,000 名没有结构性心脏病的人因心源性猝死而丧生。人们越来越多地寻找这些心源性猝死病例的遗传和后天原因，并且已发现数百种突变与促心律失常疾病长 QT (LQT) 综合征有关。大多数先天性 LQT 综合征患者的 KCNQ1 或 KCNH2（人醚 a-go-go 相关）基因存在突变，这些基因编码延迟整流 K+ 基础的电压门控 K+ 通道 1 亚基 Kv7.1 和 Kv11.1电流在心中。研究表明，KCNQ1 (LQT1) 突变和 KCNH2 (LQT2) 突变通常会导致功能丧失。许多 LQT1 和大多数 LQT2 突变导致 Kv7.1 和 Kv11.1 保留在内质网 (ER) 中，从而减少细胞表面表达的功能通道的数量。迄今为止，仅针对运输缺陷的 LQT2 突变确定了增加 ER 输出和功能表达的机制，不幸的是，这些机制中的大多数不具有治疗潜力。为了合理制定治疗运输缺陷型 LQT1 或 LQT2 突变患者的治疗策略，我们建议研究指导 LQT1 和 LQT2 突变的 ER 保留以及野生型 (WT) Kv7.1 的 ER 输出和运输的细胞特性。和 Kv11.1。我们将检验这一假设：LQT1 和 LQT2 突变的 ER 保留受到细胞质量控制的不同组成部分以及不同囊泡运输途径中 Kv7.1 和 Kv11.1 运输的调节。我们预计，调节分子伴侣、共分子伴侣和 Kv7.1 或 Kv11.1 之间的相互作用将选择性地增加不同运输缺陷 LQT1 和 LQT2 突变的功能表达，并且 Kv7.1 和 Kv11.1 的囊泡运输特性可以被操纵以增加其功能表达。公共卫生相关性：每年有多达 25,000 名没有结构性心脏病的人死于心源性猝死。这些心源性猝死病例的遗传和后天原因越来越多地被确定，数百种突变与促心律失常疾病长 QT (LQT) 综合征有关。大约七千人中就有一人患有 LQT1 或 LQT2，这分别是由 KCNQ1 或 KCNH2 基因突变引起的。这些基因编码电压门控 K+ 通道 1 亚基 Kv7.1 和 Kv11.1，它们是心脏延迟整流 K+ 电流的基础。研究表明，LQT1 和 LQT2 突变通常会导致功能丧失。功能丧失的机制各不相同，但现在人们认识到，许多突变会减少细胞表面表达的功能通道的数量，因为它们保留在细胞内的内质网 (ER) 中。迄今为止，仅针对 LQT2 确定了增加这些突变功能表达的机制，并且不具有治疗潜力。为了合理制定治疗运输缺陷LQT1或LQT2突变患者的治疗策略，我们建议研究Kv7.1和Kv11.1的细胞质量控制和囊泡运输特性。我们将测试以下假设：LQT1 和 LQT2 突变的 ER 保留受细胞质量控制的不同组成部分以及不同囊泡运输途径中的 Kv7.1 和 Kv11.1 运输的调节。我们预计我们将找到新的方法来增加运输缺陷的 LQT1 和 LQT2 突变的功能表达。