Role of GAG-Binding Proteins in Cryptosporidium Infection
GAG 结合蛋白在隐孢子虫感染中的作用
基本信息
- 批准号:9203724
- 负责人:
- 金额:$ 21.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-22 至 2018-05-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAdhesionsAminoglycoside resistanceAnimal ModelAntibodiesApicalBindingBinding ProteinsBiological ModelsC-Type LectinsCRISPR/Cas technologyCalciumCarbohydratesCell surfaceCell-Matrix JunctionCellsCharacteristicsChemistryChildClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsComplexCountryCryptosporidiosisCryptosporidiumCryptosporidium parvumCytoplasmic GranulesDiarrheaDiseaseEpithelialEpithelial CellsFutureGene TargetingGenetic EngineeringGlycoproteinsGlycosaminoglycansGoalsHeparan Sulfate ProteoglycanHumanImmunocompromised HostIn VitroInfectionInterferon Type IIInterventionIntestinal parasiteIntestinesInvadedKnock-outKnockout MiceLifeMalnutritionMediatingMembrane ProteinsModelingMolecular GeneticsMucin-2 Staining MethodMucinsOocystsParasitesPathogenesisPatientsPlasmidsPlasmodiumPlayPolysaccharidesProteinsProteoglycanProtozoaRecombinantsReportingResourcesRoleSignal TransductionSporozoitesStagingSurfaceSystemTestingToxoplasmaVulnerable Populationsbasecancer cellcell transformationdrug developmenteffective therapyextracellularin vivoinhibitor/antagonistmicrobialmouse modelnovelpathogensmall moleculevaccine developmentxylosides
项目摘要
PROJECT SUMMARY
Cryptosporidium (Crypto) causes diarrheal disease worldwide, which can be life-threatening in
immunocompromised hosts such as untreated HIV/AIDS patients and malnourished children in resource-
constrained countries. However, there is no consistently effective treatment for cryptosporidiosis in these
vulnerable populations. Our long-term goal is to understand the role of Crypto proteins involved in mediating
host cell attachment and invasion in order to develop novel interventions for cryptosporidiosis. We have
identified and characterized Clec, a unique Crypto protein with three characteristics of proteins involved in
attachment and invasion. Clec is 1) a glycosaminoglycan (GAG)-binding protein with 2) mucin-like and 3) C-
type lectin domains. The objective of this application is to elucidate the role of Clec in Crypto infection. Clec is
an extracellular type 1 membrane protein, which is conserved in C. parvum, C. hominis and C. muris, is
expressed during infection in vitro, localizes to the apical surface and dense granules of invasive stages, binds
to cell surface GAGs, specifically heparan sulfate proteoglycans (HSPGs) on intestinal epithelial cells and
blocks C. parvum attachment to and invasion of these cells via interactions with these GAGs. These findings,
strongly suggest that Clec plays a role in Crypto infection by mediating attachment and invasion and raise the
possibility that it may serve as a target for intervention. However, until recently, it was not possible to determine
the role of Crypto proteins using molecular genetics. Our central hypothesis is that Clec mediates Crypto
attachment to and invasion of intestinal epithelial cells in vitro and promotes infection in vivo by binding to cell
surface heparan sulfate proteoglycans. In this application, we propose to test this hypothesis in vitro and in
vivo using CRISPR/Cas9 mediated gene-targeting approaches recently pioneered by our collaborator, Dr.
Boris Striepen. The Specific Aims are 1) to determine the role of C. parvum Clec (CpClec) in attachment to and
invasion of human intestinal epithelial cells in vitro using gene-targeting approaches and 2) To determine the
role of CpClec in infection in vivo using animal models of cryptosporidiosis. At the completion of these aims we
expect to have established the role of CpClec in attachment and invasion in vitro and in infection in vivo using
molecular genetics and complementary approaches. Future studies will be directed at determining the role of
specific domains of Clec, and identifying and elucidating the roles of other GAG-binding Crypto proteins using
gene-targeting approaches. The long-term goal is to determine whether CpClec and/or other GAG-binding
proteins can serve as targets for drug or vaccine development.
项目摘要
隐孢子虫(Crypto)在世界范围内引起炭疽病,这可能危及生命,
免疫功能低下的宿主,如未经治疗的艾滋病毒/艾滋病患者和营养不良的儿童,
受限制的国家。然而,对于这些隐孢子虫病没有一致有效的治疗方法,
弱势群体。我们的长期目标是了解密码蛋白在介导
宿主细胞附着和侵入,以便开发新的隐孢子虫病干预措施。我们有
鉴定和表征Clec,一种独特的密码蛋白,具有三种蛋白质特征,
依恋与入侵Clec是1)糖胺聚糖(GAG)结合蛋白,具有2)粘蛋白样和3)C-
型凝集素结构域。本申请的目的是阐明Clec在Crypto感染中的作用。克莱克是
胞外1型膜蛋白,其在C. parvum、小隐翅虫C. hominis和C.穆里斯群岛
在体外感染过程中表达,定位于侵袭阶段的顶端表面和致密颗粒,结合
- 细胞表面GAG,特别是肠上皮细胞上的硫酸乙酰肝素蛋白聚糖(HSPG),
C区。细小病毒通过与这些GAG的相互作用附着和侵入这些细胞。这些发现,
这强烈表明Clec通过介导附着和侵袭,并提高细胞的粘附能力,在隐孢子虫感染中发挥作用。
它可能成为干预的目标。然而,直到最近,
用分子遗传学研究密码蛋白的作用。我们的中心假设是Clec介导了Crypto
在体外粘附和侵入肠上皮细胞,并通过与细胞结合促进体内感染
表面硫酸乙酰肝素蛋白聚糖。在本申请中,我们建议在体外和体内测试这一假设。
体内使用CRISPR/Cas9介导的基因靶向方法,最近由我们的合作者,Dr.
鲍里斯·斯特里彭具体目的是:1)确定C。parvum Clec(CpClec)附着于
使用基因靶向方法体外检测人肠上皮细胞的侵袭; 2)确定
CpClec在使用隐孢子虫病动物模型的体内感染中的作用。在完成这些目标后,我们
预期已经建立了CpClec在体外附着和侵袭以及体内感染中的作用,
分子遗传学和互补方法。未来的研究将致力于确定
Clec的特异性结构域,并使用
基因靶向方法。长期目标是确定CpClec和/或其他GAG结合蛋白是否能够抑制肿瘤的生长。
蛋白质可以作为药物或疫苗开发的目标。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Honorine D Ward其他文献
Honorine D Ward的其他文献
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{{ truncateString('Honorine D Ward', 18)}}的其他基金
An Ex Vivo 3-D Pre-Clinical Human Enteroid Model for Cryptosporidium
隐孢子虫离体 3D 临床前人类肠样模型
- 批准号:
9090036 - 财政年份:2015
- 资助金额:
$ 21.88万 - 项目类别:
O-Glycan Synthesis: Potential Targets for Intervention in Cryptosporidiosis
O-聚糖合成:干预隐孢子虫病的潜在目标
- 批准号:
8410648 - 财政年份:2012
- 资助金额:
$ 21.88万 - 项目类别:
O-Glycan Synthesis: Potential Targets for Intervention in Cryptosporidiosis
O-聚糖合成:干预隐孢子虫病的潜在目标
- 批准号:
8496716 - 财政年份:2012
- 资助金额:
$ 21.88万 - 项目类别:
Immune Response to Cryptosporidiosis in a Birth Cohorot of Children of South Indi
南印度儿童出生队列对隐孢子虫病的免疫反应
- 批准号:
8111465 - 财政年份:2010
- 资助金额:
$ 21.88万 - 项目类别:
Immune Response to Cryptosporidiosis in a Birth Cohorot of Children of South Indi
南印度儿童出生队列对隐孢子虫病的免疫反应
- 批准号:
8072937 - 财政年份:2010
- 资助金额:
$ 21.88万 - 项目类别:
Immune Response to Cryptosporidiosis in a Birth Cohorot of Children of South Indi
南印度儿童出生队列对隐孢子虫病的免疫反应
- 批准号:
7911171 - 财政年份:2009
- 资助金额:
$ 21.88万 - 项目类别:
Role of Proteases in Cryptosporidium-Host Cell Interactions
蛋白酶在隐孢子虫-宿主细胞相互作用中的作用
- 批准号:
7878271 - 财政年份:2009
- 资助金额:
$ 21.88万 - 项目类别:
Probiotics for Infectious Diarrhea in Children in South India
益生菌治疗印度南部儿童感染性腹泻
- 批准号:
7599643 - 财政年份:2008
- 资助金额:
$ 21.88万 - 项目类别:
Immune Response to Cryptosporidiosis in a Birth Cohorot of Children of South Indi
南印度儿童出生队列对隐孢子虫病的免疫反应
- 批准号:
7687425 - 财政年份:2008
- 资助金额:
$ 21.88万 - 项目类别:
Immune Response to Cryptosporidiosis in a Birth Cohorot of Children of South Indi
南印度儿童出生队列对隐孢子虫病的免疫反应
- 批准号:
7907685 - 财政年份:2008
- 资助金额:
$ 21.88万 - 项目类别:
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