Skin microbiome interactions with complement

皮肤微生物组与补体的相互作用

基本信息

批准号：
9033068
负责人：
Elizabeth Anne Grice
金额：
$ 35.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033068
关键词：
Acne Acute Address Anaphylatoxins Antibiotics Atopic Dermatitis Award C5a anaphylatoxin receptor Cells Complement Complement Membrane Attack Complex Cutaneous Data Disease Disease Outcome Flare Fluorescence-Activated Cell Sorting Foundations Gene Expression Genes Germ-Free Goals Health Immune Immune response Immunity Impaired wound healing Infection Infiltration Inflammation Inflammatory Knowledge Link Messenger RNA Microbe Modeling Mus Natural Immunity Outcome Pathway interactions Phase Phenotype Population Population Heterogeneity Propionibacterium acnes Regulation Research Resistance Role Shapes Signal Pathway Signal Transduction Skin Skin Tissue Soft Tissue Infections Staphylococcus aureus Staphylococcus epidermidis Streptococcus pyogenes Testing Therapeutic Transplantation Virulent Wound Healing Wound Infection antimicrobial peptide arm chemokine complement deficiency complement pathway cytokine deep sequencing diabetic differential expression improved keratinocyte microbial microbial community microbiota microorganism mouse model novel pathogen rRNA Genes receptor reconstitution skin disorder skin microbiome transcriptome sequencing wound

项目摘要

DESCRIPTION (provided by applicant): The skin harbors a diverse population of microbiota with important functions in cutaneous health and disease. The role of host-microbe interactions is well appreciated in multiple skin disorders. However, very little is known regarding host modulation of skin microbiota, and microbial regulation of host cutaneous immunity. We have previously shown that disrupting complement signaling alters the diversity and composition of skin microbiota in parallel with changing the cutaneous inflammatory milieu. Further, our RNA-seq studies indicate that genes related to complement signaling and activation are upregulated in conventionally raised mouse skin as compared to germ free mouse skin, suggesting that the commensal microbiota regulate their expression. Our overarching hypothesis is that there is a mechanistic link between the skin microbiota and complement. We posit that the skin microbiota are shaped and maintained by complement, and conversely, that the commensal microbiota modulate complement at the gene expression level. To test our hypothesis we propose the following aims: 1) Determine how commensals and pathogens differentially induce complement gene expression in skin. We will also determine if commensal microbiota reconstitution can tune complement gene expression and improve infection outcome in a model of skin and soft tissue infection. 2) Establish the complement effector pathways that impact cutaneous microbial composition, diversity, and quantity. Following up on preliminary data indicating that complement deficiency accelerates excisional wound healing in mouse models in parallel with shifting the colonizing microbiota, we will test the necessity and the sufficiency of the microbiot in this phenotype. Completion of the proposed studies will fill a gap in our fundamental knowledge of skin-microbe interactions, the functional consequences of disrupting these interactions, while facilitating future research questions regarding the role of skin microbiota in disease, wound healing, and infection.

描述（由适用提供）：皮肤具有多样性的微生物群，在皮肤健康和疾病中具有重要功能。在多种皮肤疾病中，宿主 - 微生物相互作用的作用得到了很好的认识。然而，关于皮肤微生物群的宿主调节以及宿主皮肤免疫学的微生物调节，知之甚少。我们以前已经表明，与改变皮肤炎症环境并行的相互补充信号传导会改变皮肤菌群的多样性和组成。此外，我们的RNA-seq研究表明，与无胚胎小鼠皮肤相比，在常规凸起的小鼠皮肤中，与补体信号传导和激活有关的基因进行了更新，这表明共生微生物群调节其表达。我们的总体假设是皮肤菌群与完成之间存在机械联系。我们认为皮肤微生物群是通过完成的形状和维护的，相反，共生微生物群调节基因表达水平的完成。为了检验我们的假设，我们提出以下目的：1）确定共生和病原体如何不同地诱导皮肤中的完整基因表达。我们还将确定在皮肤和软组织感染模型中，共生微生物群的重建是否可以调节基因表达并改善感染结果。 2）建立影响皮肤微生物组成，多样性和数量的补体效应途径。跟进初步数据，表明补体缺乏会加速与移动菌落微生物群并行的小鼠模型中的爆发性伤口愈合，我们将在该表型中测试微生物群的必要和充分性。拟议的研究的完成将填补我们对皮肤微生物相互作用的基本知识的差距，这是破坏这些相互作用的功能后果，同时促进了有关皮肤微生物群在皮肤中的作用的未来研究问题疾病，伤口愈合和感染。