Novel trypanosome receptor for thrombospondin-1

血小板反应蛋白-1 的新型锥虫受体

基本信息

批准号：
8013618
负责人：
Pius N Nde
金额：
$ 14.36万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013618
关键词：
Affect Affinity Chromatography Amino Acids Applications Grants Area Award Binding Biology Blood Cardiac Cardiovascular Pathology Cell Communication Cells Chagas Disease Chronic DNA Data Development Disease Etiology Excision Extracellular Matrix Extracellular Matrix Proteins Faculty Funding Gene Expression Genes Goals Grant Health Heart Heart Diseases Individual Infection Infection prevention International Intervention Investigation Journals Knowledge Laboratories Lead Link MALDI-TOF Mass Spectrometry Minority Modeling Molecular Molecular Profiling Molecular Target Morbidity - disease rate Mus Myocardial Infarction Oligosaccharides Parasites Pathogenesis Pathology Play Positioning Attribute Postdoctoral Fellow Process Proteins Public Health Publications Publishing RNA Interference Receptor Cell Recombinant Proteins Research Research Personnel Role Science Scientist Secure Series Staging Surface THBS1 gene Testing Thrombospondin 1 Tissues Training Trypanosoma Trypanosoma cruzi Universities Wild Type Mouse Wisconsin Work base graduate student heart cell in vivo inhibitor/antagonist innovation interest medical schools meetings microbial mortality mouse model novel novel strategies pathogen prevent programs receptor receptor binding research study sugar

项目摘要

DESCRIPTION (provided by applicant): Trypanosoma cruzi, the causative agent of Chagas' heart disease affects several million individuals causing significant morbidity and mortality, yet it remains incurable. T. cruzi modulates the gene expression profiles of a few extracellular matrix proteins to facilitate infection. One of the genes up-regulated early during infection by the parasite is host thrombospondin-1 (TSP-1), a matricellular protein. TSP-1 binds specifically to the surface of invasive forms of T. cruzi trypomastigotes and knockdown of host TSP-1 by RNA interference causes significant inhibition of T. cruzi infection. We hypothesize that the trypomastigote form of T. cruzi up- regulates host TSP-1 that interacts with trypanosome surface receptor(s) to enhance the infection of heart cells. The long-term goal of this research is to understand the molecular mechanisms that allow T. cruzi to infect heart cells, so that specific molecular intervention strategies can be developed to prevent infection of heart cells. The hypothesis will be tested by experiments based on these specific aims: 1. To clone and characterize the novel T. cruzi TSP-1 binding molecule. We will use affinity chromatography, MALDITOF-MS, PCR and purification of recombinant proteins approaches to identify, clone and characterize the trypomastigote receptor that is important in the process of T. cruzi infection; 2. To determine the in vivo role of TSP-1 gene in the process of T. cruzi infection using TSP-1 KO mice model. PUBLIC HEALTH RELEVANCE: In this project, we propose to identify and characterize a novel receptor on the surface of infectious T. cruzi trypomastigotes that binds specifically with host thrombospondin-1. This research is significant to public health because it will provide a molecular understanding of one of the first steps of infection of heart cells by infectious trypomastigotes, which will facilitate the development of specific molecular intervention strategies to prevent Chagas' heart disease.

描述（由申请人提供）：Cruzi锥虫，Chagas心脏病的病因影响数百万个个体，导致了显着的发病率和死亡率，但仍然无法治愈。 T. Cruzi调节一些细胞外基质蛋白的基因表达谱，以促进感染。寄生虫在感染早期上调的基因之一是宿主血小板蛋白-1（TSP-1），一种母细胞蛋白。 TSP-1特异性结合了Cruzi锥虫的浸润性形式的表面和通过RNA干扰对宿主TSP-1的敲低，会引起对Cruzi T. cruzi感染的显着抑制。我们假设Cruzi上的锥虫形式调节与锥虫表面受体相互作用的宿主TSP-1，以增强心脏细胞的感染。这项研究的长期目标是了解允许克鲁齐（T. cruzi）感染心脏细胞的分子机制，以便可以开发特定的分子干预策略以防止心脏细胞感染。该假设将通过基于这些特定目的的实验测试：1。克隆和表征新型T. cruzi TSP-1结合分子。我们将使用亲和色谱，Malditof-MS，PCR和重组蛋白方法的纯化来识别，克隆和表征在T. Cruzi感染过程中很重要的锥虫受体。 2。使用TSP-1 KO小鼠模型确定TSP-1基因在T. Cruzi感染过程中的体内作用。公共卫生相关性：在这个项目中，我们建议在传染性的T. cruzi锥虫表面识别和表征一种新型受体，该受体与宿主血栓形成蛋白-1专门结合。这项研究对公共卫生而言是重要的，因为它将通过传染性锥虫对心脏细胞感染的第一步之一提供分子理解，这将有助于制定特定的分子干预策略，以防止Chagas的心脏病。