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 伍德的灯检查任何患者都会发现痤疮皮杆菌，这是一种与痤疮有关的微生物。这 这项技术能刺激痤疮隐孢子菌。目前尚不清楚它们是如何或为什么分泌的，但它们会引起炎症。 并能粘合金属。光疗法可以刺激卟啉杀死痤疮念珠菌，暂时改善痤疮。 异维A酸是一种非抗菌痤疮治疗方法，可增加健康皮肤微生物和人体蛋白质，从而 限制金属。我的K08项目将检验这一假设，即这些蛋白质选择健康的皮肤微生物。我们 相信我们的发现将导致培养(而不是杀死)微生物来治愈疾病的新疗法。 候选人。从1997年高中四年级开始，我一直在培训成为一名内科科学家。在.期间 在我的医学博士学位期间，我学习了免疫学，并使用结构-功能研究来剖析宿主和病原体之间的相互作用。 这次培训让我学了皮肤科，在那里我可以看到免疫系统在每一次皮疹中发挥作用。作为一名住院医生，我 进行了一项人体研究，评估了微生物在痤疮缓解过程中的变化。我发表了这些发现， 他们现在支持我提出的K08机械学研究。我的职业目标是经营一个翻译研究实验室 研究人类和微生物之间的相互作用如何影响皮肤病。我的K08作品将建造 为这项工作奠定了科学基础，并提供了我过渡到独立所需的技能。 环境凭借出色的研究人员、合作关系和职业发展资源，华盛顿 大学医学院(WUSM)是获得K08奖项的理想机构，我将经常参加那里的活动 科学会议、职业发展研讨会和教学为我的终身教职做好准备。 我的导师(杰弗里·亨德森博士)是使用基于质谱学(MS)的代谢组学的世界专家 研究人类-微生物对金属的竞争。他有多笔NIH拨款支持这些类型的研究 并拥有广泛的专业知识，使用MS和生物化学方法研究金属和血红素代谢。 WUSM是一个从事医学研究的特殊地方，这就是我于2017年加入WUSM教职员工的原因。 研究。人类皮肤使用微生物、物理和分泌屏障来预防感染。分泌型蛋白质 可以限制金属，但它们在这个系统中的作用尚不清楚。目前也不清楚正常皮肤微生物痤疮假单胞菌是如何 获取金属或为什么它分泌卟啉，这可以结合金属(例如，血红素)并引起炎症。灯 治疗可以激活卟啉杀死痤疮念珠菌，暂时改善痤疮。一种非抗菌药物(异维甲酸) 可以治好粉刺。它增加了健康的皮肤微生物和限制金属的人类蛋白质。我假设 人类蛋白质限制金属选择健康的皮肤微生物。我将通过识别C.来检验这个假设。 痤疮途径被异维A酸丰富，并确定痤疮念珠菌是否使用卟啉或RoxP来获得金属。