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（由申请人提供）：皮肤含有对皮肤健康和疾病具有重要功能的多种微生物群。宿主-微生物相互作用在多种皮肤疾病中的作用已得到充分认识，然而，对于宿主对皮肤的调节知之甚少。我们之前已经证明，破坏补体信号传导会改变皮肤微生物群的多样性和组成，同时也会改变皮肤炎症环境。表明与无菌小鼠皮肤相比，与补体信号传导和激活相关的基因在传统饲养的小鼠皮肤中上调，这表明共生微生物群调节其表达，我们的总体假设是皮肤微生物群和补体之间存在机制联系。我们假设皮肤微生物群是由补体塑造和维持的，相反，共生微生物群在基因表达水平上调节补体。为了检验我们的假设，我们提出以下目标：1）确定如何调节补体。我们还将确定共生微生物群的重建是否可以调整皮肤和软组织感染模型中的补体基因表达并改善感染结果2）建立影响皮肤微生物组成的补体效应途径。、多样性和数量的初步数据表明，补体缺乏会加速小鼠模型中的切除伤口愈合，同时改变定植微生物群，我们将测试补体缺乏的必要性和充分性。完成拟议的研究将填补我们对皮肤-微生物相互作用、破坏这些相互作用的功能后果的基础知识的空白，同时促进有关皮肤微生物群在这种表型中的作用的未来研究问题。疾病、伤口愈合和感染。