Control Mechanisms of Human Voltage Gated Proton Channels, hHv1
人类电压门控质子通道的控制机制,hHv1
基本信息
- 批准号:10394280
- 负责人:
- 金额:$ 36.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-05-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AspartateAutoimmune DiseasesB lymphoid malignancyB-LymphocytesBacteriaBasophilsBrain InjuriesBreast cancer metastasisCRISPR/Cas technologyCellsChronic Lymphocytic LeukemiaDiseaseDrug DesignFamilyFunctional disorderGenesGrowthHealthHistamine ReleaseHistidineHumanHydrophobicityIon Channel GatingIschemic StrokeKnock-outKnowledgeLeukocytesLiquid substanceMembrane PotentialsModelingMusMutagenesisMutationNeoplasm MetastasisPlayProteinsProtonsRegulationReportingRoleScanningSignal TransductionSperm MaturationSperm MotilityStrokeStructureTestingTissuesWorkcell killingcell typecellular pathologyhuman subjecthuman tissueimprovedleukemiamalignant breast neoplasmmolecular dynamicsnovel strategiespatch clampprotonationsmall hairpin RNAsperm celltranslational studytumor growthvoltagezygote
项目摘要
Project Summary/Abstract
The voltage gated proton channel (HV1) exists in many human tissues and plays numerous roles vital
to human health. For example, it contributes to bacterial killing by white blood cells, sperm
maturation and mobility, histamine release by basophils, B lymphocyte signaling, and airway fluid
regulation. Abnormal HV1 function has been implicated in breast cancer metastasis, brain damage in
ischemic stroke, and exacerbation of chronic lymphocytic leukemia. As its gene was not reported
until 2006, HV1 is a newcomer to the voltage gated ion channel family. Finally, its structure is unique
in resembling a crucial component of all voltage-gated ion channels. This newcomer status, its
unique structure, and its essential roles in human health and disease make understanding HV1
function and dysfunction highly significant.
Directly translational studies will evaluate reported involvement of HV1 in breast cancer growth
and metastasis. Tumor growth in mice will be examined using cells with different HV1 expression
levels, ranging from complete knock-out (CRISPR/Cas9) to reduced (shRNA) to normal (WT). Our
current working hypothesis is that HV1 acts as a switch that transduces membrane potential changes
into cellular pathology. We will also build on our discovery of the involvement of HV1 in human B cells
and in chronic lymphocytic leukemia. A novel approach will be to determine the effects of mutations
indentified in human subjects with B cell malignancy.
The DeCoursey lab has been deeply involved in the study of HV1, from discovering its
existence in mammalian and human cells, to identifying its role in a number of human cells and
tissues, to finally dissecting the molecule itself to identify which parts perform the major functions.
Over the next five years we intend to pursue expanding our knowledge of this important molecule at
multiple levels, building on our recent progress. We found that the mechanism producing proton
selective conduction requires an aspartate in the center of the pore. We will test whether a
hydrophobic region plays an additional critical role using mutagenesis, patch-clamp, and molecular
dynamics simulations. We will attack the mechanisms of voltage-gating and the unique ∆pH
dependent gating that is essential to all functions of this molecule using similar approaches, but
including a detailed mechanistic model as well as a newly improved molecular dynamics approach
that determines protonation empirically rather than assuming it. We will continually refine our
knowledge of the structures of both closed and open HV1 channels, using histidine scanning
mutagenesis and NMR. Structure-function knowledge is crucial both for understanding mechanisms
and for drug design.
项目概要/摘要
电压门控质子通道 (HV1) 存在于许多人体组织中,发挥着多种重要作用
为了人类的健康。例如,它有助于白细胞、精子杀死细菌
成熟和流动性、嗜碱性粒细胞释放组胺、B 淋巴细胞信号传导和气道液体
规定。 HV1 功能异常与乳腺癌转移、脑损伤有关
缺血性中风和慢性淋巴细胞白血病的恶化。由于其基因尚未报道
直到 2006 年,HV1 都是电压门控离子通道家族的新成员。最后,它的结构独特
类似于所有电压门控离子通道的关键组成部分。这新人身份,其
独特的结构及其在人类健康和疾病中的重要作用使我们能够了解 HV1
功能和功能障碍非常重要。
直接转化研究将评估 HV1 参与乳腺癌生长的报道
和转移。将使用具有不同 HV1 表达的细胞检查小鼠的肿瘤生长
水平,范围从完全敲除 (CRISPR/Cas9) 到减少 (shRNA) 到正常 (WT)。我们的
目前的工作假设是 HV1 作为转换膜电位变化的开关
进入细胞病理学。我们还将进一步研究 HV1 参与人类 B 细胞的发现
以及慢性淋巴细胞白血病。一种新方法将是确定突变的影响
在患有 B 细胞恶性肿瘤的人类受试者中被鉴定出。
DeCoursey实验室从发现HV1以来一直深入参与HV1的研究
存在于哺乳动物和人类细胞中,以确定其在许多人类细胞中的作用和
组织,最后解剖分子本身以确定哪些部分执行主要功能。
在接下来的五年里,我们打算扩大我们对这一重要分子的了解
多个层面,以我们最近取得的进展为基础。我们发现产生质子的机制
选择性传导需要孔中心有天冬氨酸。我们将测试是否
疏水区利用诱变、膜片钳和分子生物学发挥着额外的关键作用
动力学模拟。我们将研究电压门控机制和独特的 ΔpH
依赖门控对于使用类似方法的该分子的所有功能至关重要,但是
包括详细的机械模型以及新改进的分子动力学方法
这取决于经验而不是假设质子化。我们将不断完善我们的
使用组氨酸扫描了解封闭和开放 HV1 通道的结构
诱变和核磁共振。结构-功能知识对于理解机制至关重要
以及药物设计。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Engineered high-affinity zinc binding site reveals gating configurations of a human proton channel.
- DOI:10.1085/jgp.202012664
- 发表时间:2020-10-05
- 期刊:
- 影响因子:0
- 作者:Cherny VV;Musset B;Morgan D;Thomas S;Smith SME;DeCoursey TE
- 通讯作者:DeCoursey TE
Don't dodge retraction of fraudulent papers.
不要逃避欺诈论文的撤回。
- DOI:10.1038/d41586-022-03120-w
- 发表时间:2022
- 期刊:
- 影响因子:64.8
- 作者:DeCoursey,ThomasE
- 通讯作者:DeCoursey,ThomasE
Border-wall dollars would double US cancer-research budget.
边境墙资金将使美国癌症研究预算增加一倍。
- DOI:10.1038/d41586-019-01056-2
- 发表时间:2019
- 期刊:
- 影响因子:64.8
- 作者:DeCoursey,ThomasE
- 通讯作者:DeCoursey,ThomasE
Voltage-gated proton channels exist in the plasma membrane of human oocytes.
电压门控质子通道存在于人类卵母细胞的质膜中。
- DOI:10.1093/humrep/dez178
- 发表时间:2019
- 期刊:
- 影响因子:0
- 作者:Smith,RYa;Morgan,D;Sharma,L;Cherny,VV;Tidswell,N;Molo,MW;DeCoursey,TE
- 通讯作者:DeCoursey,TE
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{{ truncateString('THOMAS E DECOURSEY', 18)}}的其他基金
Control Mechanisms of Human Voltage Gated Proton Channels, hHv1
人类电压门控质子通道的控制机制,hHv1
- 批准号:
9916761 - 财政年份:2018
- 资助金额:
$ 36.9万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 36.9万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 36.9万 - 项目类别:
Structure-Function Releationships of Voltage-Gated Proton Channels
电压门控质子通道的结构-功能关系
- 批准号:
8249834 - 财政年份:2010
- 资助金额:
$ 36.9万 - 项目类别:
Structure-Function Releationships of Voltage-Gated Proton Channels
电压门控质子通道的结构-功能关系
- 批准号:
8460040 - 财政年份:2010
- 资助金额:
$ 36.9万 - 项目类别:
Structure-Function Releationships of Voltage-Gated Proton Channels
电压门控质子通道的结构-功能关系
- 批准号:
8066327 - 财政年份:2010
- 资助金额:
$ 36.9万 - 项目类别:
Structure-Function Releationships of Voltage-Gated Proton Channels
电压门控质子通道的结构-功能关系
- 批准号:
7778167 - 财政年份:2010
- 资助金额:
$ 36.9万 - 项目类别:
Voltage-Gated Proton Channels in Human Neutrophils
人类中性粒细胞中的电压门控质子通道
- 批准号:
7074715 - 财政年份:2005
- 资助金额:
$ 36.9万 - 项目类别:
Voltage-Gated Proton Channels in Human Neutrophils
人类中性粒细胞中的电压门控质子通道
- 批准号:
7254033 - 财政年份:2005
- 资助金额:
$ 36.9万 - 项目类别:
Voltage-Gated Proton Channels in Human Neutrophils
人类中性粒细胞中的电压门控质子通道
- 批准号:
7442280 - 财政年份:2005
- 资助金额:
$ 36.9万 - 项目类别:
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