Identification of Trim5alpha cofactors

Trim5alpha 辅因子的鉴定

基本信息

批准号：
7449609
负责人：
Nathaniel R. Landau
金额：
$ 12.46万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7449609
关键词：
Affinity Affinity Chromatography Amino Acid Sequence Anti-HIV Agents Antiviral Agents Binding Biochemical Biochemical Genetics Biological Models Boxing Capsid Cell Nucleus Cell Separation Cell physiology Cells Collaborations Compatible Complex Coupled Degradation Pathway Detection Development Disruption Drosophila genus Fingers Foundations Funding Funding Mechanisms Gel Gene Targeting Generations Genes Genetic Genome Genomics Goals Grant HIV HIV Infections HIV-1 Human Human Genome Infection Infection prevention Institutes Intracellular Transport Knock-out Libraries Lysosomes Macaca mulatta Mammalian Cell Mass Spectrum Analysis Mediating Messenger RNA Methods Mission Molecular Nature Peptides Pharmacologic Substance Phenotype Play Population Principal Investigator Protein Binding Domain Proteins RNA Interference Reporting Research Institute Research Personnel Reverse Transcription Risk Role SIV Screening procedure Sequence Homology Silver Staining Small Interfering RNA Structure TSG101 gene Technology Thinking Ubiquitination Viral Virus Work Yeasts cofactor cyclin T1 follow-up genome sequencing high throughput screening improved instrument knock-down prevent programs research study size ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): TRIM5a is an antiviral host protein the mechanism of which is not yet understood. Rhesus macaque TRIM5a restricts HIV-1 but not SIV. Genetic and biochemical evidence suggest that TRIM5a binds directly to the viral capsid as the virus enters a target cell. Evidence was recently reported suggesting that the binding of TRIM5a to the incoming capsid causes a rapid uncoating of the virus, possibly resulting in a disruption to reverse transcription. The structure of TRIM5 suggests that it may act as an E3 ligase although a role for ubiquitination or capsid degradation has not been demonstrated. The proposed project seeks to derive understanding of the mechanism by which TRIM5a functions by identifying cellular proteins that are required for its antiviral function. Cellular proteins that are required for TRIM5a antiviral function will be identified by a genome-wide screen with an siRNA library that targets most of the expressed sequences in the human genome. The screen will detect siRNAs that interfere with rhesus TRIM5a function. As a secondary approach, cell proteins that form a complex with TRIM5a will be identified biochemically. The role of the proteins identified in the screen in mediating TRIM5a function will be studied by cell and molecular experiments. The specific aims of the project are the following: 1. Identify genes that are required for TRIM5a function by RNAi screening. 2. Identify proteins that physically associate with TRIM5a. 3. Determine the role of the gene products in TRIM5a antiviral function. Human cells contain a protein called TRIM5a that has the ability to prevent infection with HIV. TRIM5a is thought to attack the virus as it enters a cell by binding directly to it, although precisely how this works is not understood. The project will use a recently developed technology termed RNAi which allows researchers to selectively shut-off various functions of the cell, to discover the mechanism by which TRIM5a inhibits HIV infection. This understanding can be useful for the development of new drugs for AIDS.

描述（由申请人提供）：TRIM5A是一种抗病毒宿主蛋白，其机制尚未理解。恒河猕猴Trim5a限制了HIV-1，但不限于SIV。遗传和生化证据表明，当病毒进入靶细胞时，TRIM5A直接与病毒capsid结合。最近有证据表明，TRIM5A与传入的衣壳的结合会导致病毒的快速脱膜，可能导致逆转录的破坏。 TRIM5的结构表明它可以作为E3连接酶，尽管尚未证明泛素化或衣壳降解的作用。拟议的项目旨在通过鉴定其抗病毒功能所需的细胞蛋白来得出对TRIM5A功能的机制的理解。 TRIM5A抗病毒功能所需的细胞蛋白将通过带有siRNA库的全基因组筛选来鉴定，该筛选靶向人类基因组中的大多数表达序列。屏幕将检测到干扰恒河Trim5a功能的siRNA。作为一种次要方法，将在生物化学上鉴定出与TRIM5A复合物的细胞蛋白。细胞和分子实验将研究筛选中鉴定在介导TRIM5A功能中的蛋白质的作用。该项目的具体目的是：1。通过RNAi筛选确定TRIM5A功能所需的基因。 2。识别物理与TRIM5A物理相关的蛋白质。 3。确定基因产物在TRIM5A抗病毒功能中的作用。人类细胞包含一种称为TRIM5A的蛋白质，具有防止HIV感染的能力。认为TRIM5A通过直接与该病毒结合进入细胞时会攻击该病毒，尽管无法理解这种工作的工作原理。该项目将使用最近开发的称为RNAi的技术，该技术使研究人员可以选择性地关闭细胞的各种功能，以发现TRIM5A抑制HIV感染的机制。这种理解对于开发艾滋病的新药可能很有用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TLR7/8 agonist induces a post-entry SAMHD1-independent block to HIV-1 infection of monocytes.

DOI：
10.1186/s12977-016-0316-3
发表时间：
2016-12-01
期刊：
Retrovirology
影响因子：
3.3
作者：
Hofmann H;Vanwalscappel B;Bloch N;Landau NR
通讯作者：
Landau NR

Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5.

金黄色葡萄球菌杀白细胞素 LukED 和 HIV-1 gp120 针对 CCR5 上的不同序列决定因素。

DOI：
10.1128/mbio.02024-16
发表时间：
2016
期刊：
mBio
影响因子：
6.4
作者：
Tam,Kayan;Schultz,Megan;Reyes-Robles,Tamara;Vanwalscappel,Bénédicte;Horton,Joshua;Alonzo3rd,Francis;Wu,Beili;Landau,NathanielR;Torres,VictorJ
通讯作者：
Torres,VictorJ