Pathogenic and protective roles of strain-specific P. acnes hyaluronidases in acne

菌株特异性痤疮丙酸杆菌透明质酸酶在痤疮中的致病和保护作用

• 批准号: 10440422
• 负责人: George Y Liu
• 金额: $ 49.13万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-18 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440422
• 关键词: Acne; Acne Vulgaris; Active Sites; Address; Adolescent; Affect; Animal Model; Anti-Inflammatory Agents; Binding; Cicatrix; Clinical; Collection; Crystallization; Data; Development; Disaccharides; Disease; Enzymes; Genes; Genome; Genomics; Health; Human; Hyaluronan; Hyaluronidase; Hydrolysis; Immune; Immune response; Immunologics; In Vitro; Inflammation; Inflammatory; Modeling; Molecular Conformation; Mus; Mutation; Pathogenesis; Pathogenicity; Pathologic; Pattern; Perception; Play; Property; Propionibacterium acnes; Publishing; Reporting; Research; Role; Sebum; Skin; Skin colonization; Structure; Structure-Activity Relationship; TLR2 gene; TNFSF10 gene; Testing; Therapeutic; Vaccines; base; biophysical techniques; cytokine; experimental study; human disease; immunopathology; improved; microbiome; mouse model; mutant; prevent; skin disorder

Abstract Acne is an important skin disorder believed to be caused by skin commensal P. acnes, although how P. acnes contributes to acne is unclear. We have identified two types of hyaluronidase enzymes, made by different strains of P. acnes, that are either pro- or anti-inflammatory. Importantly, skin colonization by P. acnes strains that encode the pro-inflammatory hyaluronidase is associated with development of acne, whereas colonization with P. acnes strains that express the anti-inflammatory hyaluronidase is associated with healthy skin. In preliminary experiments, we have shown that the pro- or anti-inflammatory property of the hyaluronidases is related to the size of hyaluronan fragments generated by the enzymes. Therefore, we hypothesize that hyaluronidases influence the acne-genic potential of P. acnes by degrading hyaluronan to different sizes. To address our hypothesis, 1) we propose to investigate the structural basis of hyaluronan degradation by P. acnes hyaluronidases, binding of hyaluronan fragments to TLR2/4 and host immune responses to the hyaluronan fragments. 2) We propose to determine the contribution of both hyaluronidases to acne by testing well characterized clinical strains of P. acnes and mutant strains of P. acnes that do not express hyaluronidase, in a new mouse acne model. 3) We will also investigate hyaluronidase-based strategies for preventing or treating acne.

抽象的 痤疮是一种重要的皮肤病，据信是由皮肤共生痤疮丙酸杆菌引起的，尽管痤疮丙酸杆菌是如何引起的 导致痤疮的因素尚不清楚。我们已经鉴定出两种类型的透明质酸酶，由不同的酶制成 痤疮丙酸杆菌菌株，具有促炎或抗炎作用。重要的是，痤疮丙酸杆菌菌株在皮肤上定植 编码促炎透明质酸酶的基因与痤疮的发生有关，而定植 表达抗炎透明质酸酶的痤疮丙酸杆菌菌株与健康皮肤有关。在 初步实验，我们已经表明透明质酸酶的促炎或抗炎特性是 与酶产生的透明质酸片段的大小有关。因此，我们假设 透明质酸酶通过将透明质酸降解成不同的尺寸来影响痤疮丙酸杆菌的痤疮发生潜力。到 为了解决我们的假设，1）我们建议研究 P. 透明质酸降解的结构基础。 痤疮透明质酸酶、透明质酸片段与 TLR2/4 的结合以及宿主对 透明质酸片段。 2) 我们建议通过测试来确定两种透明质酸酶对痤疮的影响 已明确表征的痤疮丙酸杆菌临床菌株和不表达透明质酸酶的痤疮丙酸杆菌突变株， 在一个新的小鼠痤疮模型中。 3) 我们还将研究基于透明质酸酶的策略来预防或 治疗痤疮。