This proposal describes a 5-year training program for the development of an academic career in Dermatology, with a focus on furthering our understanding of how the cutaneous microbiome influences the immunobiology of the skin, using acne as a model. As principal investigator of this project, I am currently a postdoctoral researcher with training in microbiology, molecular biology, dermatology and immunology, all fields of study encompassed by this proposal, which is aimed at elucidating how Propionibacterium acnes bacteriophages can modulate the way in which this bacterium interacts with human cells in skin to trigger innate immune responses. My mentor on this project, who will oversee my career development, is Dr. Robert L. Modlin, a world-renowned immunologist and dermatologist at UCLA. Ongoing studies in his laboratory involve deciphering the mechanisms of host defense and innate immunity in skin, both of which are relevant to this proposal. Dr. Jenny Kim, who is also a dermatologist and professor at UCLA and a leading researcher in the study of the immunological basis of acne, will serve as my co-mentor. In the short-term, my objective is to elucidate how cutaneous bacteriophages can modulate the innate response to P. acnes in the context of both acne and healthy skin. My long-term career goal is to be an independent investigator in academic dermatology, and using the skin disease acne as a model, to develop a research program aimed at uncovering the mechanisms by which microorganisms interact with their hosts to trigger immune responses in the skin. Ultimately I hope to apply the insights gained from this research to develop improved therapeutics for the treatment of skin disease. This research proposal is based upon the hypothesis that the bacteriophage lysis, which involves degradation of cell wall components and the release of bacterial ligands, modulates the cutaneous innate immune response to P. acnes. In order to test this hypothesis I am proposing three specific aims. These include: 1) Elucidate innate pathways modulated by stimulation of monocytes with phage-killed P. acnes;2) Investigate the mechanism through which bacteriophages alter P. acnes-induced immune responses according to specific effects on pattern recognition receptor activation pathways;and 3) Investigate how bacteriophage infection influences host immune responses at the site of disease. It is anticipated that the proposed studies will provide novel insights into the immunobiology of the skin, as through this work, we will define the mechanisms by which cutaneous bacteriophages can modulate innate responses, leading to the induction of distinct cytokine responses and functional outcomes that can influence acne pathogenesis. The investigation of the mechanisms by which bacteriophage lysis of a bacterial host modulates the cutaneous innate immune response is a novel area of exploration, and the studies outlined in this proposal have the potential to generate new insights into the role of bacteriophages in acne, the understanding of which will be critical for the ultimate goal of developing safe and effective phage-based acne therapies.
Acne affects millions of people, and although a number of factors contribute to this disease, the skin bacterium Propionibacterium acnes has been strongly implicated in the development acne, primarily through its ability to stimulate inflammation in skin P. acnes can be attacked and killed by a group of viruses known as bacteriophages;these also reside on human skin and have a number of features suggesting they have potential as anti-acne therapeutics. In this proposal, we aim to determine the effect that killing by bacteriophages has on the cutaneous immune response to P. acnes, as this information will be critical to the development and implementation of bacteriophage-based acne treatments.