Visualization of CXCR3 allelic usage in vivo
CXCR3 等位基因体内使用的可视化
基本信息
- 批准号:7957584
- 负责人:
- 金额:$ 7.63万
- 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:2010-05-01 至 2012-04-30
- 项目状态:已结题
- 来源:
- 关键词:AllelesAllograftingAnimal ModelAnimalsAutoimmune DiseasesAutoimmune ProcessBindingBiteCD8B1 geneCXC ChemokinesCXC chemokine receptor 3CXCL10 geneCXCL11 geneCXCL9 geneCellsCommunicable DiseasesComplexCutaneousDataDendritic CellsDiseaseElementsEnsureFemaleFlow CytometryGenderGenesGoalsGonadal Steroid HormonesImageryImmuneImmune responseImmunityImmunologyImmunotherapeutic agentInfectionInfection ControlInflammationInflammatoryInflammatory ResponseInternal Ribosome Entry SiteLaboratoriesLeishmaniaLeishmania majorLeishmaniasisLeukocyte ChemotaxisLeukocytesLifeLigandsLinkLupusMapsMediatingMicroscopyModelingMouse StrainsMultiple SclerosisMusNatural Killer CellsParasitesPathogenesisPredispositionProcessRegulationRegulatory T-LymphocyteReporterResearch PersonnelResistanceRheumatoid ArthritisRoleSand FliesSex CharacteristicsSiteT-LymphocyteTechnologyViralVisceral LeishmaniasisX ChromosomeX Inactivationallograft rejectioncancer geneticscell typechemokinechemokine receptorenhanced green fluorescent proteineosinophilglobal healthin vivointerestmaleneoplasticnovelobligate intracellular parasitepathogenpublic health relevancereceptorred fluorescent proteinresponsesextool
项目摘要
DESCRIPTION (provided by applicant): The CXC chemokine receptor 3 (CXCR3) is expressed on: plasmacytoid dendritic cells (pDCs), eosinophils, NK cells, natural regulatory T cells, CD4+ and CD8+ T cells. The three main ligands of this receptor are the CXC chemokines CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC), which are produced in high levels during inflammation. CXCR3 mediates immunity against pathogens such as Leishmania major by regulating the recruitment and function of effector T cells. However, CXCR3 also contributes to the pathogenesis of allograft rejection and many autoimmune diseases by promoting recruitment of pathogenic immune cells. The CXCR3 gene is mapped to chromosome X, and is therefore subject to monoallelic expression in females through random X chromosome inactivation (XCI). However, it is well documented that a number of X-linked genes "escape" X-chromosome inactivation and are expressed from both X chromosomes. If CXCR3 is amongst the genes which escape X-inactivation in immune cells, there will be quantitative differences in CXCR3 allele expression between the sexes. This could contribute to sex-associated differences in a variety of diseases. Gender differences in susceptibility to infectious and autoimmune diseases are well documented. Females are more resistant than males to infections caused by intracellular pathogens such as Leishmania, but they are more prone to autoimmune diseases such as rheumatoid arthritis. Our laboratory is studying the role of CXCR3 in different forms of leishmaniasis and is interested in determining its contribution to gender- associated resistance of females to this disease. We are interested in visualizing CXCR3 alleles that are used by different immune cells in females in vivo to determine whether the CXCR3 gene undergoes X-inactivation or escapes it. Our ability to study this complex process in vivo will be greatly enhanced if we are able to track CXCR3 expressing cells in mice and simultaneously visualize the alleles responsible for CXCR3 expression. The goals of this RO3 application are to generate a CXCR3-EFGP/RFP (CXCR3EGFP/RFP) dual reporter mouse carrying CXCR3 alleles which are linked to EGFP and RFP, respectively (Aim 1), and then to track the use of CXCR3 alleles in immune cells using an experimental L. major infection model (Aim 2). We have recently generated a CXCR3-bicistronic EGFP reporter (CIBER) mouse which expresses CXCR3 linked to enhanced green fluorescent protein (EGFP) via a viral IRES element. Our preliminary data show that CXCR3 expressing cells can be easily tracked in CIBER mice by flow cytometry and microscopy. In this project, we will generate a CXCR3-red fluorescent protein (RFP) reporter mouse and then cross it with a CIBER mouse to obtain a CXCR3EGFP/RFP mouse. This dual reporter mouse will carry one CXCR3 allele linked to EGFP and the other to RFP. Our preliminary data and the availability of CIBER mice demonstrate the feasibility of accomplishing the goals of this project within 2 years. CXCR3 EGFP/RFP reporter mice will allow us to visualize the differential expression of CXCR3 alleles in various immune cell types during infection. These mice will also be invaluable tools for other investigators to study the in vivo role of CXCR3 in infectious, inflammatory and neoplastic diseases.
PUBLIC HEALTH RELEVANCE: The CXC chemokine receptor 3 is critical of leukocyte chemotaxis and inflammation associated with infection and autoimmune diseases. This project will develop a novel mouse strain which will allow visualization of CXCR3 expressing cells and study regulation of CXCR3 gene in living animal during inflammation and infection. This information will be important for developing immunotherapeutic approaches to treat inflammatory and infectious diseases.
描述(由申请人提供):CXC趋化因子受体3 (CXCR3)表达于:浆细胞样树突状细胞(pDCs)、嗜酸性粒细胞、NK细胞、自然调节性T细胞、CD4+和CD8+ T细胞。该受体的三个主要配体是CXC趋化因子CXCL9 (Mig), CXCL10 (IP-10)和CXCL11 (I-TAC),它们在炎症期间大量产生。CXCR3通过调节效应T细胞的募集和功能介导对利什曼原虫等病原体的免疫。然而,CXCR3也通过促进致病性免疫细胞的募集参与同种异体移植排斥和许多自身免疫性疾病的发病机制。CXCR3基因定位于X染色体,因此在女性中通过随机X染色体失活(XCI)受单等位基因表达影响。然而,有充分的证据表明,许多X连锁基因“逃脱”了X染色体失活,并在两个X染色体上表达。如果CXCR3是免疫细胞中逃避x失活的基因之一,则CXCR3等位基因在两性之间的表达量存在差异。这可能会导致多种疾病的性别相关差异。对传染性和自身免疫性疾病易感性的性别差异有充分的记录。女性比男性更能抵抗细胞内病原体(如利什曼原虫)引起的感染,但她们更容易患上自身免疫性疾病,如类风湿关节炎。我们的实验室正在研究CXCR3在不同形式的利什曼病中的作用,并有兴趣确定其对女性对这种疾病的性别相关抗性的贡献。我们感兴趣的是观察雌性体内不同免疫细胞使用的CXCR3等位基因,以确定CXCR3基因是否经历x失活或逃避它。如果我们能够在小鼠体内追踪CXCR3表达细胞并同时可视化负责CXCR3表达的等位基因,我们在体内研究这一复杂过程的能力将大大增强。本RO3应用的目标是生成CXCR3- efgp /RFP (CXCR3EGFP/RFP)双报告小鼠,分别携带与EGFP和RFP相关的CXCR3等位基因(Aim 1),然后使用实验性L. major感染模型追踪CXCR3等位基因在免疫细胞中的使用(Aim 2)。我们最近培育了一种通过病毒IRES元件表达与增强型绿色荧光蛋白(EGFP)相关的CXCR3-双链EGFP报告基因(CIBER)小鼠。我们的初步数据表明,通过流式细胞术和显微镜可以很容易地追踪CIBER小鼠中表达CXCR3的细胞。在本项目中,我们将生成一只cxcr3 -红色荧光蛋白(RFP)报告小鼠,然后与CIBER小鼠杂交,得到一只CXCR3EGFP/RFP小鼠。这种双报告小鼠将携带一个与EGFP相关的CXCR3等位基因,另一个与RFP相关。我们的初步数据和CIBER小鼠的可用性证明了在2年内完成该项目目标的可行性。CXCR3 EGFP/RFP报告小鼠将使我们能够可视化在感染期间各种免疫细胞类型中CXCR3等位基因的差异表达。这些小鼠也将成为其他研究人员研究CXCR3在感染性、炎症性和肿瘤性疾病中的体内作用的宝贵工具。
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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Abhay R Satoskar其他文献
Molecular characterization and genetic diversity of cutaneous leishmaniasis from North Eastern Pakistan
- DOI:
10.1016/j.actatropica.2021.105964 - 发表时间:
2021-09-01 - 期刊:
- 影响因子:
- 作者:
Nargis Shaheen;Chaitenya Verma;Thalia Pacheco-Fernandez;Greta Volpedo;Aneeqa Hamid;Ismail Zeb;Syed Aizaz Ali Shah;Shah Fahad;Attiya Iqbal;Asma Ashraf;Amjad Khan;Misbah Gul;Muhammad Ilyas Khan;Huma Fatima;Muhammad Afzal;Abhay R Satoskar;Naveeda Akhter Qureshi - 通讯作者:
Naveeda Akhter Qureshi
Abhay R Satoskar的其他文献
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{{ truncateString('Abhay R Satoskar', 18)}}的其他基金
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Visualization of CXCR3 allelic usage in vivo
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Discovery of novel antileishmanial molecules from the plant Pentalinon andreuxii
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8083173 - 财政年份:2010
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使用 Pentalinon andrieuxii 根提取物治疗皮肤利什曼病
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