Structure-Function Studies of Tight Junction Membrane Proteins
紧密连接膜蛋白的结构-功能研究
基本信息
- 批准号:8152114
- 负责人:
- 金额:$ 47.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-30 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Tight junctions have three critically important functions in both epithelia and endothelia. Tight junctions form the paracellular barrier that separates body compartments, they act as a fence that maintains apical-basolateral polarity of the cell, and they have paracellular pores that allow selective permeation of ions and small molecules across the cell monolayer. Three integral membrane proteins are thought to play a central role in these functions of the tight junction and hence are of high biological interest: claudin (a multigene family with 24 members), occludin, and tricellulin. The long-term goal of this proposal is to solve the structure of each of these proteins at atomic resolution and to use structure-guided mutagenesis to elucidate the structural mechanisms underlying their unique functions.
The PI has already assembled a multidisciplinary team of investigators from Los Angeles, Pittsburgh,
Boston, and Berlin to tackle the challenging problem of unraveling the function of claudins. This team has unique expertise in assaying paracellular pore function by electrophysiological methods, visualizing tight junction structure by freeze fracture electron microscopy, and hybrid molecular/Brownian dynamics
modeling of pore function.
The PI previously established a collaboration with the laboratory of Dr. Robert Stroud to express claudin proteins with the goal of crystallization, and has made significant progress. Thus,
the applicants constitute a team that is uniquely poised to partner with a PSI Biology Network Center for
Membrane Protein Structure Determination to tackle the structure determination and functional
characterization of tight junction membrane proteins.
Aim 1. Solve the structure of claudin by X-ray crystallography
Aim 2. Determine the molecular basis of the pore functions of claudin
Aim 3. Determine the structural basis of the barrier and fence functions of claudin
Aim 4. Structure-function comparisons of tight junction membrane proteins
PUBLIC HEALTH RELEVANCE: Tight junctions are junctions between cells that are needed for epithelia (e.g. skin, kidney, intestine) to act as barriers. This proposal would determine the structure of proteins in the membrane of the tight junction and use this information to elucidate the mechanism by which they function. This work has widespread significance for understanding diseases due to epithelial barrier dysfunction.
DESCRIPTION (provided by applicant): Tight junctions have three critically important functions in both epithelia and endothelia. Tight junctions form the paracellular barrier that separates body compartments, they act as a fence that maintains apical-basolateral polarity of the cell, and they have paracellular pores that allow selective permeation of ions and small molecules across the cell monolayer. Three integral membrane proteins are thought to play a central role in these functions of the tight junction and hence are of high biological interest: claudin (a multigene family with 24 members), occludin, and tricellulin. The long-term goal of this proposal is to solve the structure of each of these proteins at atomic resolution and to use structure-guided mutagenesis to elucidate the structural mechanisms underlying their unique functions.
The PI has already assembled a multidisciplinary team of investigators from Los Angeles, Pittsburgh,
Boston, and Berlin to tackle the challenging problem of unraveling the function of claudins. This team has unique expertise in assaying paracellular pore function by electrophysiological methods, visualizing tight junction structure by freeze fracture electron microscopy, and hybrid molecular/Brownian dynamics
modeling of pore function.
The PI previously established a collaboration with the laboratory of Dr. Robert Stroud to express claudin proteins with the goal of crystallization, and has made significant progress. Thus,
the applicants constitute a team that is uniquely poised to partner with a PSI Biology Network Center for
Membrane Protein Structure Determination to tackle the structure determination and functional
characterization of tight junction membrane proteins.
Aim 1. Solve the structure of claudin by X-ray crystallography
Aim 2. Determine the molecular basis of the pore functions of claudin
Aim 3. Determine the structural basis of the barrier and fence functions of claudin
Aim 4. Structure-function comparisons of tight junction membrane proteins
PUBLIC HEALTH RELEVANCE: Tight junctions are junctions between cells that are needed for epithelia (e.g. skin, kidney, intestine) to act as barriers. This proposal would determine the structure of proteins in the membrane of the tight junction and use this information to elucidate the mechanism by which they function. This work has widespread significance for understanding diseases due to epithelial barrier dysfunction.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Alan S Yu其他文献
Alan S Yu的其他文献
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{{ truncateString('Alan S Yu', 18)}}的其他基金
Biomedical Research Core 3 - Clinical Research Core
生物医学研究核心 3 - 临床研究核心
- 批准号:
10475048 - 财政年份:2020
- 资助金额:
$ 47.3万 - 项目类别:
Biomedical Research Core 3 - Clinical Research Core
生物医学研究核心 3 - 临床研究核心
- 批准号:
10059768 - 财政年份:2020
- 资助金额:
$ 47.3万 - 项目类别:
Biomedical Research Core 3 - Clinical Research Core
生物医学研究核心 3 - 临床研究核心
- 批准号:
10214616 - 财政年份:2020
- 资助金额:
$ 47.3万 - 项目类别:
Biomedical Research Core 3 - Clinical Research Core
生物医学研究核心 3 - 临床研究核心
- 批准号:
10686076 - 财政年份:2020
- 资助金额:
$ 47.3万 - 项目类别:
Role of claudin-2 in Calcium Homeostasis and Kidney Stone Disease
Claudin-2 在钙稳态和肾结石疾病中的作用
- 批准号:
10238078 - 财政年份:2019
- 资助金额:
$ 47.3万 - 项目类别:
Role of claudin-2 in Calcium Homeostasis and Kidney Stone Disease
Claudin-2 在钙稳态和肾结石疾病中的作用
- 批准号:
10020951 - 财政年份:2019
- 资助金额:
$ 47.3万 - 项目类别:
Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) IV: Prognosis for End-Stage Renal Disease and Biomarker Validation
多囊肾病放射影像研究联盟 (CRISP) IV:终末期肾病的预后和生物标志物验证
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9906761 - 财政年份:2017
- 资助金额:
$ 47.3万 - 项目类别:
CRISP III - Kansas Polycystic Kidney Imaging Program Supplemental Request
CRISP III - 堪萨斯州多囊肾成像计划补充请求
- 批准号:
9269449 - 财政年份:2016
- 资助金额:
$ 47.3万 - 项目类别:
Randomized, controlled pilot study of nicotinamide in polycystic kidney disease
烟酰胺治疗多囊肾病的随机对照试验研究
- 批准号:
8807460 - 财政年份:2015
- 资助金额:
$ 47.3万 - 项目类别:
Randomized, controlled pilot study of nicotinamide in polycystic kidney disease
烟酰胺治疗多囊肾病的随机对照初步研究
- 批准号:
9136856 - 财政年份:2015
- 资助金额:
$ 47.3万 - 项目类别:
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