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: 10585915
• 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/10585915
• 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; Dryness; 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; Modeling; Nutritional Immunity; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phototherapy; Physicians; Porphyrins; Positioning Attribute; Predisposition; Propionibacterium; Propionibacterium acnes; Protein Secretion; 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; 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.

项目总结/摘要 伍德的灯检查任何病人将揭示痤疮皮肤杆菌，微生物与痤疮。这 技术使C.痤疮卟啉。目前尚不清楚它们是如何或为何分泌的，但它们会引起炎症 并且可以结合金属。光疗法可激发卟啉类物质杀死C.痤疮和暂时改善痤疮。 异维甲酸是一种非抗菌痤疮治疗，增加健康的皮肤微生物和人类蛋白质， 限制金属。我的K 08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培养（而不是杀死）微生物来治疗疾病的新疗法。 候选人从1997年我高中四年级开始，我就一直在接受医学科学家的培训。期间 医学博士哲学博士、我学的是免疫学，用结构-功能研究来剖析宿主-病原体的相互作用。 这种训练让我去了皮肤科，在那里我可以看到免疫系统在每一个皮疹中起作用。作为一名居民，我 进行了一项人体研究，评估微生物如何在痤疮缓解中变化。我发表了这些发现， 他们现在支持我提出的K 08机制研究。我的职业目标是管理一个转化研究实验室 研究人类和微生物之间的相互作用如何影响皮肤病。我的K 08工作将建立 科学的基础，并提供我需要过渡到独立的技能。 环境凭借出色的研究人员、合作精神和职业发展资源，华盛顿 大学医学院（WUSM）是K 08奖的理想机构，我将经常参加 科学会议，职业发展研讨会，和教学法，为终身教职做准备。 我的导师（Jeffrey亨德森博士）是一位世界级的专家，擅长使用基于质谱（MS）的代谢组学来 研究人类和微生物对金属的竞争。他有多个国家卫生研究院的赠款支持这些类型的研究 并拥有广泛的专业知识，使用MS和生物化学方法来研究金属和血红素代谢。 WUSM是一个特殊的地方追求医学研究，这就是为什么我在2017年加入WUSM教师。 Research.人类皮肤利用微生物、物理和分泌屏障来防止感染。分泌蛋白 可以限制金属，但它们在这个系统中的作用尚不清楚。目前还不清楚正常的皮肤微生物C。痤疮 获得金属或为什么它分泌卟啉，它可以结合金属（如血红素）和引起炎症。光 治疗激活卟啉杀死C.痤疮和暂时改善痤疮。一种非抗菌药物（异维甲酸） 可以治疗痤疮。它增加了健康的皮肤微生物和限制金属的人体蛋白质。我假设 人类蛋白质限制金属以选择健康的皮肤微生物。我将通过识别C来检验这个假设。 痤疮途径富集异维甲酸和确定是否C.痤疮使用卟啉或RoxP来获取金属。