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: 8727066
• 负责人: THOMAS E DECOURSEY
• 金额: $ 32.91万
• 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/8727066
• 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。它能够使NADPH氧化酶快速活性，从而产生活性氧物种(ROS)。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，从而导致与炎症损伤有关的各种顽固病理，包括神经退行性疾病和纤维化疾病(例如阿尔茨海默病)、一些癌症、动脉粥样硬化、高血压和组织排斥反应。因此，hHV1的功能影响了许多炎症相关的退行性疾病，这些疾病的治疗和治疗不充分或不存在。由于必须保存对微生物病原体的先天免疫反应，因此控制ROS的策略不能完全取消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ROS。除了对ROS的影响外，hHV1还在嗜碱性粒细胞、鼻黏膜、精子和B细胞中发挥其他功能，这些功能与男性生育、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物，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hHV1水平的降低降低了转移的侵袭性。这一发现表明，通过抑制hHV1来阻止乳腺癌是可能的。这个项目将确定质子通道如何发挥作用的关键，即在排除所有其他离子的同时，将质子转移到细胞膜上。我们最近发现了质子通道的“选择性过滤器”的位置，但它的基本特征，极端的质子选择性，其机制仍然是个谜。这一机制的分子细节，我们将在拟议的工作中进行研究，将提供设计针对hHV1功能的治疗所需的基本信息。我们将改变蛋白质的特定部分，并通过实验研究这些改变的影响。我们还将使用计算机模拟来预测和解释质子选择性机理。在与纳迪姆·哈拉布博士和约书亚·雅各布斯(拉什大学医学中心)的合作下，我们将使用人工关节排斥反应作为hHV1功能的病理生理学模型。我们将以未来药物可能改变的方式改变hHV1的功能，并将评估对单个细胞和生理系统的影响。