Lysosomal maturation during periodontal infections

牙周感染期间溶酶体的成熟

• 批准号: 8388158
• 负责人: Kathleen Boesze-Battaglia
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-12 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8388158
• 关键词: Actinobacillus actinomycetemcomitans; Agonist; Autophagocytosis; Autophagosome; Bacteria; Cathepsin L; Cathepsins; Cell surface; Cells; Cholesterol; Chronic; Complex; Defense Mechanisms; Degradation Pathway; Disease; Ensure; Environment; Felis catus; Host Defense; Host Defense Mechanism; Hydrolase; Immune response; Immune system; Infection; Inflammation; Inflammatory; Link; Lipids; Lysosomes; Mediating; Membrane Microdomains; Microbe; Molecular; Monitor; Myelogenous; Pathway interactions; Periodontal Infection; Periodontitis; Phagolysosome; Phagosomes; Porphyromonas gingivalis; Process; Proteins; Role; Sentinel; Signal Pathway; Sorting - Cell Movement; Systemic disease; TLR2 gene; TLR4 gene; Testing; Therapeutic; Toll-Like Receptor 2; Up-Regulation; Vesicle; base; design; macrophage; novel; pathogen; toll-like receptor 4; trafficking; uptake; vacuolar H+-ATPase

DESCRIPTION (provided by applicant): Periodontitis is a chronic inflammatory disease that is driven by polymicrobial infection by red-complex periodontal pathogens, the best characterized of which is P. gingivalis (P.g.). To establish chronic infection in hostile host environments pathogens devise mechanisms by which they evade or subvert host defense mechanisms designed to eliminate them, one such mechanism is lysosome mediated degradation. We propose that P. gingivalis subverts phagolysosome degradation by hijacking the autophagosomal pathway to create a protective intracellular niche in macrophages. Specifically, we will test the hypothesis that upregulation of autophagosome formation is critical for P. gingivalis survival in macrophages and requires MREG mediated lysosomal maturation. In specific aim 1 we will test the hypothesis that P. g. sequesters into autophagosomes and confers protection from lysosomal degradation. In specific aim 2 we focus on how the mode of P. g. entry into macrophages contributes to its trafficking profile and persistence. Specific aim 3 will focus on the LPS-TLR mediated signaling pathways contributing to lysosome maturation as it relates to autophagy. PUBLIC HEALTH RELEVANCE: As sentinels of the immune system, macrophages function to eliminate pathogens through degradative processes as part of the host immune response. Numerous bacterial pathogens subvert these processes to persist, survive and in some cases replicate allowing for their dissemination thereby contributing to systemic disease. In these studies we will investigate the molecular mechanism by which a perio-pathogen, P.gingivalis evades the host defense mechanism by sequestration into none degradative compartments. Formation of these compartments requires a novel regulator of lysosome (degradative) function called melanoregulin. Understanding how melanoregulin contributed to pathogen degradation will allow us to develop therapeutic approaches to enhancing lysosome function during chronic infection.

描述（由申请人提供）：牙周炎是一种慢性炎症性疾病，是由红色复杂性牙周病原体驱动的。为了在敌对的宿主环境中建立慢性感染病原体，通过这种机制来逃避或颠覆旨在消除它们的宿主防御机制，一种这样的机制是溶酶体介导的降解。我们建议牙龈疟原虫通过劫持自噬体途径来颠覆吞噬体降解，从而在巨噬细胞中创建保护性细胞内小裂。具体而言，我们将检验以下假设：自噬体形成的上调对于巨噬细胞中的牙龈牙龈疟原虫的存活至关重要，并且需要MREG介导的溶酶体成熟。在特定目标1中，我们将检验P. G的假设。隔离为自噬体，并赋予防止溶酶体降解的保护。在特定目标2中，我们关注P. G的模式。进入巨噬细胞有助于其贩运和持久性。具体目标3 将重点放在LPS-TLR介导的信号通路上，导致与自噬相关的溶酶体成熟。 公共卫生相关性：作为免疫系统的前哨，巨噬细胞通过降解过程消除病原体，作为宿主免疫反应的一部分。许多细菌病原体颠覆了这些过程以持续，生存和在某些情况下复制，从而允许它们传播，从而导致全身性疾病。在这些研究中，我们将研究分子机制，通过隔离为无降解区室，通过将第八病原原理（gyivalis）逃避了宿主防御机理。这些区室的形成需要一种称为黑兰雷格蛋白的溶酶体（降解）功能的新型调节剂。了解黑素调节蛋白如何促进病原体降解将使我们能够开发出治疗方法来增强慢性感染期间溶酶体功能。