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Novel role and function of Paneth cell PYY in anti-fungal innate immunity

潘氏细胞PYY在抗真菌先天免疫中的新作用和功能

基本信息

批准号：
8983958
负责人：
Joseph F PIERRE
金额：
$ 5.42万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8983958
关键词：
Affect Age Animals Anti-Bacterial Agents Antibodies Antifungal Agents Area Biomedical Research Brain Stem Caco-2 Cells Candida albicans Cell Culture Techniques Cell physiology Charge Cholinergic Agents Circadian Rhythms Clinical Confocal Microscopy Crohn&apos s disease Cytoplasmic Granules Cytosol Data Defect Dendritic Cells Diagnosis Disease Enteroendocrine Cell Epithelium Fungal Components Gender Gene Expression Germ-Free Goals Growth Human Hyphae In Vitro Intestines Mass Spectrum Analysis Microbial Biofilms Microscopy Morphology Movement Mucous body substance Mus Natural Immunity Oral Organism Paneth Cells Pathogenesis Pathogenicity Peptides Periodicity Physiological Physiology Population Production Proteins Regulation Research Resolution Role Satiation Stimulus Testing Tissues Training Virulence Virulent Wild Type Mouse Work Yeasts antimicrobial antimicrobial peptide base career development fungus gut microbiota in vivo insight laser capture microdissection member microbial microbiome microorganism novel pathogen peptide hormone prevent protein structure public health relevance response tyrosyltyrosine

项目摘要

DESCRIPTION (provided by applicant): Peptide tyrosine tyrosine (PYY) is a highly conserved molecule in vertebrate organisms with diverse regulatory roles, including satiety, circadian rhythmicity, and intestinal physiology. It was previously thought that PYY was exclusively found in intestinal enteroendocrine cells (EECs), the brain stem, and epidermal dendritic cells. We now find that PYY appears to be expressed in small intestinal Paneth cells, raising the possibility that PYY has an additional role as an antimicrobial peptide. This possibility is furthe supported by similarities in the protein structure and charge distribution of PYY to other antimicrobial compounds. Additionally, upon stimulation with microbial products, ex vivo ileal tissues from conventionally raised (CONV) mice release PYY into culture, while tissues from germ-free (GF) animals does not, analogous to other antimicrobial peptides that are regulated by and involved in microbial assemblage. However, we find that PYY (0-25uM) does not appear to have anti-bacterial effects, but rather a selective action in inhibiting hyphae formation in Candida albicans, an important human fungal member and potential pathogen of the gut microbiota. Non-hyphae expressing fungi, or yeast, were unaffected by PYY. Based on these observations, we hypothesize that PYY is an important and selective antimicrobial compound that modulates the virulence of eukaryotic microorganisms of the intestinal microbiome. To test this hypothesis, we propose the following aims: (1) to characterize the regulation of Paneth cell PYY expression and release in response to stimulus and the localization and concentrations of PYY within the intestinal mucous and luminal compartments, and (2) to investigate the effect of PYY upon C. albicans hyphae formation (GFP-tagged), gene expression, and pathogenicity against human Caco-2 cell culture. We believe this work has the potential to be paradigm shifting in showing alternative roles for gut peptides such as PYY in host regulation of intestinal fungal organisms. These studies will also provide further training and opportunities in new research areas that will continue the applicant's career development in academic biomedical research.

描述（由申请人提供）：肽酪氨酸酪氨酸（PYY）是脊椎动物中高度保守的分子，具有多种调节作用，包括饱腹感、昼夜节律和肠道生理学。此前人们认为 PYY 只存在于肠内分泌细胞 (EEC)、脑干和表皮树突细胞中。我们现在发现 PYY 似乎在小肠潘氏细胞中表达，这增加了 PYY 作为抗菌肽的额外作用的可能性。 PYY 与其他抗菌化合物的蛋白质结构和电荷分布的相似性进一步支持了这种可能性。此外，在用微生物产品刺激后，传统饲养（CONV）小鼠的离体回肠组织将 PYY 释放到培养物中，而无菌（GF）动物的组织则不会，类似于受微生物组合调节并参与微生物组合的其他抗菌肽。然而，我们发现 PYY (0-25uM) 似乎不具有抗菌作用，而是具有选择性抑制白色念珠菌菌丝形成的作用，白色念珠菌是重要的人类真菌成员和肠道微生物群的潜在病原体。非菌丝表达真菌或酵母不受 PYY 影响。基于这些观察结果，我们假设 PYY 是一种重要的选择性抗菌化合物，可调节肠道微生物组真核微生物的毒力。为了检验这一假设，我们提出以下目标：(1) 表征潘氏细胞 PYY 表达和释放对刺激的调节以及 PYY 在肠粘膜和腔室内的定位和浓度，(2) 研究 PYY 对白色念珠菌菌丝形成（GFP 标记）、基因表达和对人 Caco-2 细胞培养物的致病性的影响。我们相信这项工作有可能改变范式，展示肠道肽（例如 PYY）在宿主肠道调节中的替代作用。真菌生物。这些研究还将提供新研究领域的进一步培训和机会，从而继续申请人在学术生物医学研究方面的职业发展。