Mechanistic Investigations of Sebaceous Skin Microbial Community Remodeling in Acne Remission

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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.