Effect of bacteriophages on cutaneous inflammation in acne

描述（由申请人提供）：该提案描述了一个为期5年的皮肤病学学术生涯发展培训计划，重点是进一步了解皮肤微生物组如何影响皮肤的免疫生物学，以痤疮为模型。作为该项目的首席研究员，我目前是一名博士后研究员，接受过微生物学、分子生物学、皮肤学和免疫学的培训，这些都是本提案所涵盖的研究领域，旨在阐明痤疮丙酸杆菌噬菌体如何调节这种细菌与皮肤中人类细胞相互作用的方式，从而引发先天免疫反应。我在这个项目上的导师是Robert L. Modlin博士，他将监督我的职业发展，他是加州大学洛杉矶分校世界知名的免疫学家和皮肤科医生。他的实验室正在进行的研究包括破译宿主防御和皮肤先天免疫的机制，这两者都与这一提议有关。珍妮·金博士是加州大学洛杉矶分校的皮肤科医生和教授，也是痤疮免疫学基础研究的主要研究员，她将作为我的共同导师。在短期内，我的目标是阐明皮肤噬菌体如何在痤疮和健康皮肤的背景下调节对痤疮假体的先天反应。我的长期职业目标是成为一名学术皮肤科的独立研究者，并以皮肤疾病痤疮为模型，开展一项研究计划，旨在揭示微生物与宿主相互作用以触发皮肤免疫反应的机制。最终，我希望应用从这项研究中获得的见解来开发更好的治疗皮肤病的方法。本研究建议是基于噬菌体裂解的假设，包括细胞壁成分的降解和细菌配体的释放，调节皮肤对痤疮假单胞杆菌的先天免疫反应。为了验证这一假设，我提出了三个具体目标。这些包括：1)阐明由噬菌体杀死的痤疮假单胞菌刺激单核细胞所调节的先天通路；2)通过对模式识别受体激活途径的特异性作用，探讨噬菌体改变痤疮杆菌诱导的免疫应答的机制；3)研究噬菌体感染如何影响疾病部位宿主的免疫反应。我们预计，拟议的研究将为皮肤免疫生物学提供新的见解，因为通过这项工作，我们将定义皮肤噬菌体调节先天反应的机制，从而诱导不同的细胞因子反应和影响痤疮发病机制的功能结果。研究噬菌体裂解细菌宿主调节皮肤先天免疫反应的机制是一个新的探索领域，本提案中概述的研究有可能对噬菌体在痤疮中的作用产生新的见解，对其的理解对于开发安全有效的基于噬菌体的痤疮治疗的最终目标至关重要。

DESCRIPTION (provided by applicant): 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.