Mechanistic Investigations of Sebaceous Skin Microbial Community Remodeling in Acne Remission

痤疮缓解中皮脂皮肤微生物群落重塑的机制研究

• 批准号: 10113544
• 负责人: William Howard McCoy IV
• 金额: $ 15.92万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10113544
• 关键词: Acne; Acne Vulgaris; Affect; Anaerobic Bacteria; Antibiotics; Award; Binding; Biochemical; Biological Process; Biology; Chelating Agents; Clinical; Communities; Dairy Products; Dermatology; Disease; Disease remission; Doctor of Medicine; Doctor of Philosophy; Environment; Exanthema; Faculty; Foundations; Funding; Genes; Genome; Genomics; Goals; Grant; Growth; Heme; Hemolysin; Human; Immune system; Immunology; Infection; Infection prevention; Inflammation; Inflammatory; Institution; Investigation; Iron; Isotretinoin; Leukocyte L1 Antigen Complex; Light; Mass Spectrum Analysis; Medical Research; Mentors; Metabolic; Metabolic Pathway; Metabolism; Metagenomics; Metal exposure; Metals; Microbe; Micronutrients; Nutritional Immunity; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phototherapy; Physicians; Porphyrins; Positioning Attribute; Predisposition; Propionibacterium; Propionibacterium acnes; Proteins; Publishing; Research; Research Design; Research Personnel; Resource Development; Role; Running; Sampling; Scientist; Secure; Skin; Skin colonization; Structure; Sunlight; Swab; System; Techniques; Testing; Trace metal; Training; Transition Elements; Translational Research; United States; United States National Institutes of Health; Universities; Virulence Factors; Virulent; Washington; Wood material; Work; base; career; career development; chelation; commensal bacteria; consumer product; cost; experience; gene synthesis; heme-binding protein; high school; human pathogen; human study; improved; medical schools; meetings; metabolomics; metal chelator; metal metabolism; microbial; microorganism growth; novel; novel therapeutics; oxidation; pathogen; pressure; psoriasin; response; skills; skin disorder; skin microbiome; skin microbiota; tenure track; transcriptome sequencing; water conservation

PROJECT SUMMARY/ABSTRACT Wood’s lamp examination of any patient will reveal Cutibacterium acnes, the microbe associated with acne. This technique excites C. acnes porphyrins. It is not known how or why they are secreted, but they cause inflammation and can bind metals. Light therapy can excite porphyrins to kill C. acnes and temporarily improve acne. Isotretinoin is a non-antimicrobial acne treatment that increases healthy skin microbes and human proteins that limit metals. My K08 project will test the hypothesis that these proteins select for healthy skin microbes. We believe that our findings will lead to new therapies that cultivate (rather than kill) microbes to cure disease. Candidate. I have been training to be a physician scientist since my senior year of high school in 1997. During my M.D.-Ph.D., I studied immunology and used structure-function studies to dissect host-pathogen interactions. This training led me to dermatology where I can see the immune system at work in every rash. As a resident, I conducted a human study assessing how microbes change in acne remission. I published these findings and they now support my proposed K08 mechanistic studies. My career goal is to run a translational research lab that studies how interactions between humans and microbes impact skin disease. My K08 work will build the scientific foundation for this work and provide the skills that I need to transition to independence. Environment. With exceptional researchers, collegiality, and career development resources, Washington University School of Medicine (WUSM) is an ideal institution for a K08 award, where I will attend frequent scientific meetings, career development seminars, and didactics to prepare myself for a tenure-track position. My mentor (Dr. Jeffrey Henderson) is a world-expert in using mass spectrometry(MS)-based metabolomics to study human-microbe competition over metals. He has multiple NIH grants supporting these types of studies and has extensive expertise using MS and biochemical approaches to study metal and heme metabolism. WUSM is an exceptional place to pursue medical research and that is why I joined the WUSM faculty in 2017. Research. Human skin uses microbial, physical, and secreted barriers to prevent infection. Secreted proteins can limit metals, but their role in this system is unclear. It is also unclear how the normal skin microbe C. acnes acquires metals or why it secretes porphyrins, which can bind metals (e.g. heme) and cause inflammation. Light therapy activates porphyrins to kill C. acnes and temporarily improve acne. A non-antimicrobial drug (isotretinoin) can cure acne. It increases healthy skin microbes and human proteins that limit metals. I hypothesize that human proteins limit metals to select for healthy skin microbes. I will test this hypothesis by identifying C. acnes pathways enriched by isotretinoin and determining if C. acnes uses porphyrins or RoxP to acquire metals.

项目摘要/摘要 伍德对任何患者的灯灯检查都会显示痤疮痤疮，这是与痤疮有关的微生物。这 技术激发C.痤疮卟啉。尚不知道它们是如何或为什么被分泌的，但它们会引起创新 并可以结合金属。光治疗可以激发卟啉杀死痤疮孢子并暂时改善痤疮。 异维诺蛋白是一种非抗菌痤疮治疗，可增加健康的皮肤微生物和人类蛋白质 极限金属。我的K08项目将测试这些蛋白质选择健康皮肤微生物的假设。我们 相信我们的发现将导致新疗法培养（而不是杀死）微生物以治愈疾病。 候选人。自1997年高中以来，我就一直在培训成为一名物理科学家。 我的医学博士学位，我研究了免疫学并使用结构功能研究来剖析宿主 - 病原体相互作用。 这项训练使我进入了皮肤病学，我可以看到每一次皮疹的免疫系统。作为居民，我 进行了一项人类研究，评估微生物如何改变痤疮的缓解。我发表了这些发现， 他们现在支持我提出的K08机械研究。我的职业目标是运营一个翻译研究实验室 研究人类与微生物之间的相互作用如何影响皮肤疾病。我的K08工作将建立 这项工作的科学基础，并提供了我需要过渡到独立的技能。 环境。华盛顿拥有卓越的研究人员，合作和职业发展资源 大学医学院（WUSM）是K08奖的理想机构，我将参加频率 科学会议，职业发展中心和教学法，为自己做好统治地位做好准备。 我的心理（Jeffrey Henderson博士）是使用质谱（MS）代谢组学的世界专家 研究金属的人类微型竞争。他有多个支持这类研究的NIH赠款 并使用MS和生化方法具有广泛的专业知识来研究金属和血红素代谢。 WUSM是从事医学研究的杰出场所，这就是为什么我在2017年加入WUSM教职员工的原因。 研究。人体皮肤使用微生物，物理和分泌障碍物来防止感染。分泌的蛋白质 可以限制金属，但是它们在该系统中的作用尚不清楚。还不清楚正常皮肤微生物C.痤疮如何 获取金属或为什么它分泌可以结合金属（例如血红素）并引起注射的卟啉的原因。光 治疗会激活卟啉以杀死痤疮梭菌并暂时改善痤疮。一种非抗菌药物（异维诺蛋白） 可以治愈痤疮。它增加了限制金属的健康皮肤微生物和人类蛋白质。我假设这一点 人蛋白限制金属以选择健康的皮肤微生物。我将通过识别C来检验该假设。 异托摩酸富含的痤疮途径并确定痤疮梭菌是否使用卟啉或ROXP获取金属。