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LincRNAs in Mucosal Defense to AIDS Opportunistic Pathogen Cryptosporidium

LincRNA 在粘膜防御艾滋病机会病原体隐孢子虫中的作用

基本信息

批准号：
10289715
负责人：
Xian-Ming Chen
金额：
$ 39.25万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-11-06 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10289715
关键词：
AIDS-Related Opportunistic Infections Acquired Immunodeficiency Syndrome Address Attenuated B lymphocyte-induced maturation protein 1 Biochemical Biology Cells Child Country Cryptosporidiosis Cryptosporidium Developing Countries Development Diarrhea Effector Cell Epigenetic Process Epithelial Epithelial Cells Genes Genetic Transcription Goals HIV Infections HIV diagnosis Health Health Services Accessibility Highly Active Antiretroviral Therapy Human Immune Immunity Immunotherapeutic agent In Vitro Incidence Infection Interferon Type II Intestines Mediating Modeling Molecular Morphology Mucosal Immune Responses Mucosal Immunity Mucous Membrane Neonatal Outcome PRDM1 gene Parasites Pathogenesis Patients Pattern recognition receptor Persons Predisposition Production RNA Binding RNA-Binding Proteins Receptor Signaling Regulation Regulatory Element Research Role Series Signal Transduction Site Surface TLR4 gene Testing Therapeutic Intervention Untranslated RNA antimicrobial base cell type chemokine chromatin modification chromatin remodeling cytokine design effective therapy experience gastrointestinal gastrointestinal epithelium immunoreaction in vivo innovation intestinal epithelium knock-down microbial minimally invasive new therapeutic target novel novel therapeutic intervention opportunistic pathogen overexpression pathogen prevent response transcription factor

项目摘要

Summary Cryptosporidium remains a significant AIDS-related opportunistic infection among people with late HIV diagnosis or without access to HAART. This parasite infects the gastrointestinal (GI) epithelium in humans; infection is also a common cause of diarrhea in young children in developing countries. There is currently no fully effective therapy available for the infection. This parasite has been referred as a “minimally invasive” mucosal pathogen, and epithelial antimicrobial defense is key to mucosal innate anti-Cryptosporidium immunity. Whereas it is well appreciated that IFN-γ is required for preventing development of intestinal cryptosporidiosis, the key cellular regulatory elements that determine IFN-γ-mediated GI epithelial anti- Cryptosporidium defense, as well as its association with the high susceptibility of infection in AIDS patients and in young children, remain unknown. Our recent studies demonstrate that IFN-γ-mediated epithelial anti- Cryptosporidium defense requires the induction of specific long intergenic non-coding RNAs (lincRNAs) in epithelial cells. Specifically, we have identified several lincRNAs that are expressed strictly in epithelial cells. Expression levels of several epithelial lincRNAs are upregulated in GI epithelial cells following Cryptosporidium infection. Knockdown of selected epithelial lincRNAs attenuated IFN-γ-mediated epithelial anti-Cryptosporidium defense. Based on these observations, we hypothesize that induction of epithelial lincRNAs in GI epithelial cells upon pattern-recognition receptors signaling promotes mucosal anti-Cryptosporidium immunity through priming epithelial cells for IFN-γ-mediated epithelial antimicrobial defense. We will use in vitro and in vivo infection models and complementary biochemical, molecular, and morphologic approaches to define the transcription of epithelial lincRNA genes upon pattern-recognition receptor signaling in GI epithelial cells following Cryptosporidium infection (Aim 1), elucidate the molecular mechanisms by which epithelial lincRNAs promote IFN-γ-mediated epithelial anti-cryptosporidial defense (Aim 2), and decipher the roles of specific RNA- binding proteins in modulating IFN-γ-mediated anti-cryptosporidial defense in GI epithelial cells through their interactions with epithelial lincRNAs (Aim 3). The proposal is conceptually innovative as it tests new concepts regarding mucosal antimicrobial defense and the pathogenesis of intestinal cryptosporidiosis, relevant to the design and implementation of new therapeutic strategies.

总结隐孢子虫仍然是艾滋病晚期感染者中一种重要的艾滋病相关机会性感染诊断或无法获得HAART。这种寄生虫感染人的胃肠道（GI）上皮; 感染也是发展中国家幼儿腹泻的常见原因。目前没有有效的治疗方法。这种寄生虫被称为“微创” 粘膜病原体和上皮抗菌防御是粘膜先天性抗隐孢子虫的关键免疫力然而，很好地理解，IFN-γ是防止肠上皮细胞发生所需的。隐孢子虫病，决定IFN-γ介导的胃肠道上皮抗隐孢子虫防御，以及它与艾滋病患者感染的高易感性的关系，在幼儿中，仍然未知。我们最近的研究表明，IFN-γ介导的上皮抗-IFN-γ，隐孢子虫的防御需要诱导特定的长基因间非编码RNA（lincRNA），上皮细胞具体而言，我们已经鉴定了几种严格在上皮细胞中表达的lincRNA。隐孢子虫感染后胃肠道上皮细胞中几种上皮lincRNA的表达水平上调感染敲除选定的上皮lincRNA减弱IFN-γ介导的上皮抗隐孢子虫防御基于这些观察，我们假设在胃肠道上皮细胞中诱导上皮lincRNA，细胞对模式识别受体的信号传导促进粘膜抗隐孢子虫免疫，引发上皮细胞进行IFN-γ介导的上皮抗微生物防御。我们将在体外和体内感染模型和互补的生物化学，分子和形态学方法来定义胃肠道上皮细胞中上皮lincRNA基因转录对模式识别受体信号传导的影响在隐孢子虫感染后（目的1），阐明上皮lincRNA 促进IFN-γ介导的上皮抗隐孢子虫防御（Aim 2），并破译特异性RNA- 结合蛋白通过其在调节IFN-γ介导的抗隐孢子虫防御中的作用与上皮lincRNA的相互作用（Aim 3）。该提案在概念上是创新的，因为它测试了新的概念关于粘膜抗菌防御和肠道隐孢子虫病的发病机制，设计和实施新的治疗策略。