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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.

项目概要原生动物寄生虫克氏锥虫是恰加斯病的病原体，恰加斯病是一种被忽视的热带病导致患者严重发病、死亡和经济负担的疾病。这种疾病，最初在拉丁美洲国家流行，现在已成为所有主要国家的新的全球健康问题现代全球化带来的经济发达国家。约 30% 的克氏锥虫感染者最终出现心脏、胃肠道和/或神经系统疾病或其组合。巨结肠是恰加斯病的主要病理之一，伴有扩大的纤维化胃肠道消化道和胃肠道运动障碍。克氏锥虫感染引起心脏、胃肠道疾病的机制受影响个体的神经系统疾病仍在调查中。本提案的目的的目的是破译早期感染期间克氏锥虫失调的分子机制，这些机制有助于巨结肠病理学。河马信号通路已被确定为纤维化疾病的一个促成因素跨组织类型。下游河马效应分子 YAP 的激活启动纤维化的转录基因。我们最近表明，T. cruzi 在感染早期阶段激活 YAP 核翻译。心脏内皮细胞。先前研究表明，Thombospondin-1 (TSP-1) 会被寄生虫上调以利于感染。心脏内皮细胞中 TSP-1 的敲除降低了 YAP 平均荧光细胞核内的强度，表明 TSP-1 在 T 期间与 hippo 信号通路积极相互作用。克鲁兹感染。 PIWI 相互作用 RNA (piRNA) 是一类小非编码 RNA，有助于胃肠道胃癌、结肠癌、结直肠癌等疾病。我们最近证明 piRNA 可以靶向并调节参与克氏锥虫发病机制的基因，例如 TGFB1、FOS 和 NFATC2。然而，尚未研究克氏锥虫感染期间结肠细胞中 piRNA 的作用。根据这些观察，我们假设寄生虫在早期阶段失调了河马信号通路和 piRNA 的感染。该假设将通过以下具体目标进行评估：（1）评估 T. cruzi 感染早期的 hippo 信号通路以及 (2) 评估 piRNA 和 PIWIL 的作用感染早期调节下游促纤维化基因的蛋白质。这个项目是意义重大，因为它将：确定河马信号在克氏锥虫感染结肠细胞期间的作用；描绘 TSP-1 和河马信号在寄生虫感染期间相互作用；表征 PIWIL 蛋白的功能作用使用原代人结肠上皮和平滑肌显示 piRNA 在感染过程中增加细胞。在进修培训期间，我将能够巩固和获得新的技术技能，为撰写手稿，并参与科学传播、科学写作等职业发展活动，和教学。梅哈里医学院和梅哈里-范德比尔特联盟为此提供了设备项目。