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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由申请人提供）：电压门控质子通道（hHV1）在人体内的许多细胞中起着至关重要的作用。它使 NADPH 氧化酶快速活跃，产生活性氧 (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，细胞产生过多的活性氧，这会导致与炎症损伤相关的多种棘手病症，包括神经退行性和纤维化疾病（例如阿尔茨海默病）、某些癌症、动脉粥样硬化、高血压和组织排斥。因此，hHV1 功能会影响许多与炎症相关的退行性疾病，而这些疾病的治愈和治疗方法不充分或根本不存在。由于必须保留对微生物病原体的先天免疫反应，因此控制 ROS 的策略不得完全消除 ROS 的产生。质子通道是理想的药物靶点，因为消除其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 在嗜碱性粒细胞、鼻粘膜、精子和 B 细胞中还具有其他功能，这些功能与男性生育能力、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 的干预措施可以充当抗组胺药、治疗哮喘以及作为男性避孕药。最近的一份报告表明，hHV1 在转移性乳腺癌组织中高表达，并表明通过降低 hHV1 水平可以减少转移侵袭。这一发现表明通过抑制 hHV1 来阻止乳腺癌的可能性。该项目将确定质子通道如何发挥作用的关键，即使质子穿过细胞膜，同时排除所有其他离子。我们最近发现了质子通道“选择性过滤器”的位置，但其基本特征（极端质子选择性）的机制仍然是个谜。我们将在拟议的工作中研究该机制的分子细节，它将提供设计针对 hHV1 功能的疗法所需的基本信息。我们将改变蛋白质的特定部分，并通过实验研究改变的影响。我们还将使用计算机模型来预测和解释质子选择性机制。与博士合作。 Nadim Hallab 和 Joshua Jacobs（拉什大学医学中心），我们将使用人工关节排斥作为 hHV1 功能的病理生理学模型。我们将以未来药物可能的方式改变 hHV1 功能，并且我们将评估对单个细胞和生理系统的影响。