Selectivity and Permeation in the Human Voltage-gated Proton Channel, hHv1

人类电压门控质子通道 hHv1 的选择性和渗透

• 批准号: 8500709
• 负责人: THOMAS E DECOURSEY
• 金额: $ 34.99万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500709
• 关键词: Academic Medical Centers; Acids; Alzheimer' s Disease; Anions; Antihistamines; Asthma; Atherosclerosis; B-Lymphocytes; Bacteria; Basophils; Biological Models; Cell membrane; Cells; Characteristics; Charge; Chicago; Child; Collaborations; Computer Simulation; Cystic Fibrosis; Degenerative Disorder; Devices; Disease; Drug Targeting; Engineering; Fertility; Fluorescence Resonance Energy Transfer; Future; Goals; Health; Homologous Gene; Homology Modeling; Hospitals; Human; Human body; Hypertension; Immune response; Individual; Inflammation; Inflammatory; Intervention; Investigation; Ions; Joints; Left; Leukocytes; Link; Location; Lupus; Male Contraceptions; Male Contraceptive Agents; Malignant Neoplasms; Measures; Metal Binding Site; Metals; Michigan; Modeling; Molecular; Mutation; NADPH Oxidase; Nerve Degeneration; Occupations; Osteoclasts; Osteolysis; Parasites; Pathology; Phagocytes; Pharmaceutical Preparations; Physiological; Play; Positioning Attribute; Process; Production; Property; Proteins; Protons; Reactive Oxygen Species; Relative (related person); Replacement Arthroplasty; Reporting; Rest; Role; Scanning; Site; Sodium Chloride; Specificity; Structural Models; Structure of mucous membrane of nose; Suppressor Mutations; System; Testing; Tissues; Transmembrane Domain; Universities; Work; allergic response; base; bone loss; cell killing; enzyme activity; fungus; killings; macrophage; male; malignant breast neoplasm; microbial; molecular dynamics; monocyte; mutant; novel strategies; pH Homeostasis; pathogen; prevent; public health relevance; response; sensor; small molecule; sperm cell; therapy design; voltage

DESCRIPTION (provided by applicant): The voltage gated proton channel (hHV1) plays crucial roles in many cells in the human body. It enables rapid activity of the enzyme NADPH oxidase that produces reactive oxygen species (ROS). ROS produced by NADPH oxidase in white blood cells help kill bacteria, fungi, parasites, and other microbial invaders. However, in some situations, cells produce too much ROS, which results in a wide variety of intractable pathologies linked to inflammation damage, including neurodegenerative and fibrotic diseases (e.g., Alzheimer's disease), some cancers, atherosclerosis, hypertension, and tissue rejection. hHV1 function thus impacts numerous inflammation-associated degenerative diseases for which cures and treatments are inadequate or nonexistent. Because the innate immune response to microbial pathogens must be preserved, strategies to control ROS must not abolish ROS production completely. The proton channel is an ideal drug target, because eliminating its activity reduces but does not abolish ROS production by white cells. In addition to its effect on ROS, hHV1 has other functions in basophils, nasal mucosa, sperm, and B cells that implicate it in male fertility, allergic responses, and such diseases as cystic fibrosis, asthma, and lupus. Thus, interventions that modulate hHV1 could act as antihistamines, provide treatments of asthma, and serve as male contraceptives. A recent report indicates high hHV1 expression in metastatic breast cancer tissues, and showed that metastatic invasion was reduced by lowering hHV1 levels. This finding suggests the possibility of stopping breast cancer by hHV1 inhibition. This project will determine the key to how the proton channel does its job, which is moving protons across cell membranes, while excluding all other ions. We recently discovered the location of the "selectivity filter" of the proton channel, but the mechanism of its fundamental characteristic, extreme proton selectivity, remains enigmatic. The molecular details of this mechanism, which we will investigate in the proposed work, will provide the essential information needed to design therapies directed against hHV1 function. We will change specific parts of the protein and investigate the effects of the changes experimentally. We will also use computer modeling to predict and explain the proton selectivity mechanism. In collaboration with Drs. Nadim Hallab and Joshua Jacobs (Rush University Medical Center), we will use artificial joint rejection as a pathophysiological model of hHV1 function. We will alter hHV1 function in ways that future drugs might, and we will evaluate effects on both individual cells and the physiological system.

描述（申请人提供）：电压门控质子通道（hHV1）在人体许多细胞中起着至关重要的作用。它使酶NADPH氧化酶产生活性氧（ROS）的快速活性。白细胞中NADPH氧化酶产生的ROS有助于杀死细菌、真菌、寄生虫和其他微生物入侵者。然而，在某些情况下，细胞产生过多的ROS，导致与炎症损伤相关的各种顽固性病理，包括神经退行性和纤维化疾病（如阿尔茨海默病）、某些癌症、动脉粥样硬化、高血压和组织排斥。因此，hHV1功能影响了许多与炎症相关的退行性疾病，这些疾病的治疗和治疗方法不足或根本不存在。因为必须保留对微生物病原体的先天免疫反应，所以控制ROS的策略不能完全消除ROS的产生。质子通道是一个理想的药物靶点，因为消除它的活性会减少但不会消除白细胞产生的活性氧。除了对活性氧的作用外，hHV1在嗜碱性细胞、鼻黏膜、精子和B细胞中也有其他功能，这与男性生育能力、过敏反应以及囊性纤维化、哮喘和狼疮等疾病有关。因此，调节hHV1的干预措施可以作为抗组胺药，提供哮喘治疗，并作为男性避孕药。最近的一份报告表明，hHV1在转移性乳腺癌组织中高表达，并表明降低hHV1水平可以减少转移性侵袭。这一发现提示了通过抑制hHV1抑制乳腺癌的可能性。这个项目将确定质子通道如何工作的关键，质子通道在细胞膜上移动质子，同时排除所有其他离子。我们最近发现了质子通道的“选择性过滤器”的位置，但其基本特征的机制，极端的质子选择性，仍然是谜。这一机制的分子细节，我们将在拟议的工作中进行研究，将为设计针对hHV1功能的治疗方法提供必要的信息。我们将改变蛋白质的特定部分，并通过实验研究这些变化的影响。我们也将使用计算机模型来预测和解释质子的选择性机制。在与博士合作。Nadim Hallab和Joshua Jacobs (Rush University Medical Center)，我们将使用人工关节排斥作为hHV1功能的病理生理模型。我们将以未来药物可能的方式改变hHV1功能，我们将评估对个体细胞和生理系统的影响。