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.

项目概要/摘要 对任何患者进行伍德灯检查都会发现痤疮皮肤杆菌，这是一种与痤疮相关的微生物。这 该技术激发痤疮丙酸杆菌卟啉。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 并能结合金属。光疗可以激发卟啉杀死痤疮丙酸杆菌，暂时改善痤疮。 异维A酸是一种非抗菌痤疮治疗药物，可增加健康皮肤微生物和人类蛋白质， 限制金属。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 相信我们的发现将带来培养（而不是杀死）微生物来治愈疾病的新疗法。 候选人。从 1997 年高中四年级起，我就开始接受成为一名医师科学家的培训。 在我的医学博士-博士学位期间，我研究了免疫学并利用结构功能研究来剖析宿主与病原体的相互作用。 这次培训让我进入了皮肤科，在那里我可以看到免疫系统在每次皮疹中发挥作用。作为一名居民，我 进行了一项人体研究，评估微生物在痤疮缓解中如何变化。我发表了这些发现并 他们现在支持我提出的 K08 机制研究。我的职业目标是经营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 K08 作品将构建 这项工作的科学基础，并提供我过渡到独立所需的技能。 环境。华盛顿拥有杰出的研究人员、同事关系和职业发展资源 大学医学院 (WUSM) 是获得 K08 奖项的理想机构，我会经常在那里参加 科学会议、职业发展研讨会和教学，为自己获得终身教职做好准备。 我的导师（Jeffrey Henderson 博士）是一位世界级专家，擅长使用基于质谱 (MS) 的代谢组学来 研究人类与微生物对金属的竞争。他拥有多项 NIH 拨款支持这些类型的研究 并拥有使用质谱和生化方法研究金属和血红素代谢的丰富专业知识。 WUSM 是进行医学研究的绝佳场所，这就是我于 2017 年加入 WUSM 教师的原因。 研究。人类皮肤利用微生物、物理和分泌屏障来预防感染。分泌蛋白 可以限制金属，但它们在该系统中的作用尚不清楚。目前还不清楚正常皮肤微生物痤疮丙酸杆菌如何 获取金属或为什么它会分泌卟啉，卟啉可以结合金属（例如血红素）并引起炎症。光 疗法激活卟啉来杀死痤疮丙酸杆菌并暂时改善痤疮。非抗菌药物（异维A酸） 可以治疗痤疮。它可以增加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对健康皮肤微生物的选择。我将通过识别 C 来检验这个假设。 痤疮杆菌途径被异维A酸富集，并确定痤疮杆菌是否使用卟啉或 RoxP 来获取金属。