Molecular mechanisms of Trypanosoma cruzi induced colon pathogenesis

克氏锥虫诱导结肠发病的分子机制

基本信息

批准号：
10543421
负责人：
Kayla Rayford
金额：
$ 4.77万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-09 至 2023-12-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543421
关键词：
Affect Americas Apoptosis Binding Bioinformatics Biological Assay Biological Markers CRISPR/Cas technology Canada Cardiac Cardiac Myocytes Cell Nucleus Cell Proliferation Cell model Cells Central America Chagas Disease Chronic Chronic Disease Collaborations Colon Colon Carcinoma Colorectal Cancer Communicable Diseases Communication Complex Country Disease Economic Burden Educational process of instructing Endothelial Cells Epithelial Cells Epithelium Equipment Event Evolution Fellowship Fibrosis Fluorescence Fluorescent in Situ Hybridization Gastrointestinal Diseases Gastrointestinal tract structure Gene Expression Gene Expression Profile Genes Goals HIV/AIDS Heart Heart Diseases Human Immunofluorescence Immunologic Individual Infection Inflammation International Intervention Investigation Knock-out Knowledge Latin American Life Manuscripts Mediating Megacolon Modeling Modernization Molecular Morbidity - disease rate Natural Disasters Nuclear Nuclear Translocation Organ Organ Size Outcome Parasites Parasitic infection Pathogenesis Pathology Pathway interactions Patients Phase Phosphorylation Play Proteins RNA Regulation Role Signal Pathway Signal Transduction Smooth Muscle Myocytes South America TGFB1 gene Technical Expertise Testing Thrombospondin 1 Tissues Training Transcription Initiation Translations Travel Trypanosoma cruzi United States Untranslated RNA Visualization Western Blotting Writing biomarker discovery career combat comparison control gastrointestinal global health malignant stomach neoplasm medical schools migration mortality motility disorder neglected tropical diseases nervous system disorder novel organ growth piRNA protein expression targeted treatment therapeutic target therapeutically effective

项目摘要

Project Summary The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease which causes severe morbidity, mortality, and economic burden in afflicted individuals. The disease, originally endemic in Latin American countries, has now become a new global health problem in all major economically advanced countries due to modern globalization. About 30% of T. cruzi infected individuals eventually present with cardiac, gastrointestinal tract and/or neurological disorders or a combination thereof. Megacolon, one of Chagas disease major pathologies, is accompanied by an enlarged, fibrotic gastrointestinal tract and GI motility disorders. The mechanisms through which T. cruzi infection causes cardiac, gastrointestinal and neurological disorders in afflicted individuals remains under investigation. The objective of this proposal is to decipher the molecular mechanisms dysregulated by T. cruzi during early infection that contribute to megacolon pathology. The hippo signaling pathway has been identified as a contributor to fibrotic disease across tissue types. Activation of downstream hippo effector molecule YAP initiates transcription of fibrotic genes. We recently showed that T. cruzi activates YAP nuclear translation during the early phase of infection of heart endothelial cells. Thombospondin-1 (TSP-1) was previously shown to be upregulated by the parasite in order to facilitate infection. Knockout of TSP-1 in heart endothelial cells decreased YAP mean fluorescence intensity within the nucleus, indicating that TSP-1 actively interacts with the hippo signaling pathway during T. cruzi infection. PIWI-interacting RNAs (piRNAs), a class of small noncoding RNAs, contribute to gastrointestinal diseases such as gastric cancer, colon cancer, and colorectal cancer. We recently showed that piRNAs can target and regulate genes involved in T. cruzi pathogenesis, such as TGFB1, FOS, and NFATC2. However, the role of piRNAs have not been investigated in colon cells during T. cruzi infection. Based on these observations, we hypothesize that the parasite dysregulates the hippo signaling pathway and piRNAs during the early phase of infection. The hypothesis will be evaluated with the following specific aims: (1) Evaluate the dysregulation of hippo signaling pathway during early phase of T. cruzi infection and (2) Asses the role of piRNAs and PIWIL proteins in the regulation of downstream profibrotic genes during the early phase of infection. This project is significant because it will: identify the role of hippo signaling during T. cruzi infection of colon cells; delineate TSP-1 and hippo signaling interplay during parasite infection; characterize the functional roles of PIWIL proteins and piRNAs shown to be increased during infection using primary human colon epithelial and smooth muscle cells. During the fellowship training period, I will be able to solidify and gain new technical skills, prepare manuscripts, and participate in career developing activities such as scientific communication, scientific writing, and teaching. Meharry Medical College and Meharry-Vanderbilt alliance provide access to equipment for this project.

项目摘要原生动物寄生虫锥虫克鲁兹是chagas病的病因，这是一种被忽视的热带疾病会导致患病患者的严重发病，死亡率和经济负担。疾病，最初在拉丁美洲国家流行，现在已成为所有主要的全球健康问题由于现代全球化，经济上发达的国家。约有30％的克鲁兹感染的人最终出现心脏，胃肠道和/或神经系统疾病或其组合。 Megacolon是Chagas病主要病理之一，伴随着纤维化的胃肠道区域和胃肠道运动障碍。克鲁兹感染的机制导致心脏，胃肠道受苦个体中的神经系统疾病仍在研究中。该提议的目的是在早期感染期间破译被t. cruzi失调的分子机制致巨型病理学。河马信号通路已被确定为纤维化疾病的贡献者跨组织类型。下游河马效应分子yap的激活启动了纤维化的转录基因。我们最近表明，克鲁兹在感染的早期阶段激活YAP核翻译心脏内皮细胞。先前证明了Thombospondin-1（TSP-1）被寄生虫上调为了促进感染。心脏内皮细胞中TSP-1的敲除降低YAP平均荧光细胞核内的强度，表明TSP-1在T期间与河马信号通路相互作用。克鲁兹感染。 PIWI相互作用RNA（PIRNA）是一类小型非编码RNA，有助于胃肠道胃癌，结肠癌和大肠癌等疾病。我们最近表明pirnas可以靶标和调节参与Cruzi发病机理的基因，例如TGFB1，FOS和NFATC2。但是，在克鲁兹感染期间，在结肠细胞中尚未研究PIRNA的作用。基于这些观察，我们假设寄生虫在早期的河马信号通路和PIRNA失调感染。该假设将通过以下特定目的进行评估：（1）评估失调的失调克鲁兹感染的早期阶段的河马信号通路和（2）pirnas和piwil的作用在感染的早期，在调节下游纤维化基因的蛋白质中。这个项目是意义重大，因为它会：确定河马信号传导在结肠细胞的克鲁兹感染过程中的作用；描绘寄生虫感染期间的TSP-1和河马信号转导相互作用；表征piwil蛋白的功能作用使用原发性结肠上皮和平滑肌在感染过程中显示出刺激性的PIRNA 细胞。在奖学金培训期间，我将能够巩固和获得新的技术技能，准备手稿，并参与开发诸如科学沟通，科学写作，和教学。 Meharry医学院和Meharry-Vanderbilt联盟为此提供了设备的访问权限项目。