Effect of bacteriophages on cutaneous inflammation in acne

噬菌体对痤疮皮肤炎症的影响

• 批准号: 9116713
• 负责人: Laura Jane Marinelli
• 金额: $ 13.26万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116713
• 关键词: Acetylmuramyl-Alanyl-Isoglutamine; Acne; Affect; Area; Bacteria; Bacteriophages; Binding; Cell Differentiation process; Cell Wall; Cells; Clinical; Complement; Cutaneous; Cytolysis; Dendritic Cells; Dermatologist; Dermatology; Development; Disease; Family; Genes; Genetic Variation; Goals; Health; Host Defense Mechanism; Human; Immune; Immune response; Immunobiology; Immunologist; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Instruction; Investigation; Laboratories; Lesion; Life; Ligands; Mediating; Mentored Research Scientist Development Award; Mentors; Microbiology; Modeling; Molecular Biology; Molecular Profiling; Natural Immunity; Nucleotides; Pathogenesis; Pathway interactions; Pattern recognition receptor; Peptidoglycan; Peripheral Blood Mononuclear Cell; Phagocytosis; Principal Investigator; Program Development; Propionibacterium acnes; Receptor Activation; Research; Research Personnel; Research Proposals; Role; Site; Skin; System; T cell response; TLR2 gene; Testing; Therapeutic; Training; Training Programs; Transcript; Up-Regulation; Virus; Work; antimicrobial; antimicrobial peptide; base; career; career development; chemokine; cytokine; endolysin; field study; functional outcomes; genetic signature; improved; insight; killings; macrophage; marenostrin; microbial; microorganism; monocyte; novel; professor; programs; receptor; response; skin disorder; skin microbiome; transcriptome sequencing

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.

描述(由申请人提供)：这份建议书描述了一项为期5年的皮肤病学术生涯发展培训计划，重点是以痤疮为模型，加深我们对皮肤微生物群如何影响皮肤免疫生物学的理解。作为这个项目的首席研究员，我目前是一名博士后研究员，接受过微生物学、分子生物学、皮肤病学和免疫学的培训，这项建议涵盖了所有研究领域，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的人类细胞相互作用的方式，以触发先天免疫反应。我在这个项目上的导师是加州大学洛杉矶分校世界著名的免疫学家和皮肤科医生罗伯特·L·莫德林博士，他将监督我的职业发展。他的实验室正在进行的研究涉及破译宿主防御和皮肤天然免疫的机制，这两个机制都与这一提议相关。珍妮·金博士也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领军人物，她将担任我的联合导师。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单胞菌的先天反应。我的长期职业目标是成为一名学术皮肤病学的独立研究员，并以皮肤病痤疮为模型，开发一个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的研究计划。最终，我希望应用从这项研究中获得的见解来开发治疗皮肤病的改进疗法。这项研究是基于一种假设，即噬菌体的裂解作用，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菌的先天免疫反应。为了检验这一假设，我提出了三个具体目标。这包括：1)阐明噬菌体灭活痤疮杆菌刺激单核细胞所调节的先天途径；2)根据对模式识别受体激活途径的特定作用，研究噬菌体改变痤疮杆菌诱导的免疫反应的机制；3)研究噬菌体感染如何影响发病部位的宿主免疫反应。预计拟议的研究将为皮肤的免疫生物学提供新的见解，因为通过这项工作，我们将确定皮肤噬菌体调节先天性反应的机制，导致诱导不同的细胞因子反应和功能结果，从而影响痤疮的发病机制。对细菌宿主的噬菌体裂解调节皮肤天然免疫反应的机制的研究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，对其了解将对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。