权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mast cells in skin innate immune defense

皮肤先天免疫防御中的肥大细胞

基本信息

批准号：
10552573
负责人：
Anna Di Nardo
金额：
$ 50.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10552573
关键词：
Ablation Area Atopic Dermatitis Bacteria Binding Sites Biochemical Biological Assay Biology Biophysics Blood CCL2 gene CRISPR/Cas technology Cell Maturation Code Collaborations Data Data Analyses Dendritic Cells Dermal Dermis Development Disease Environment Exhibits Failure Fibroblasts Gene Expression Genes Goals Homeostasis Human Hypersensitivity IL8 gene Immune Immune response Immunity In Vitro Infection Inflammation Inflammatory Inflammatory Response Innate Immune System Interleukin-10 Interleukin-13 Interleukin-4 Interleukins Literature Measures Mediating Mediator Microbe Modeling NFKBIA gene Organism Pathway interactions Peptides Phenotype Protein Secretion Publishing Role Science Signal Transduction Skin TLR2 gene Therapeutic Virus Work commensal bacteria conditioning cytokine design dysbiosis fighting in vivo Model insight mast cell microbiome novel prevent receptor response skin disorder transcriptome

项目摘要

ABSTRACT We have demonstrated that mast cells entering the skin change phenotype triggered by contact with dermal fibroblasts (DF). In the skin, Mast Cells (MCs) down regulate their TLR2 and increase the expression of genes that downregulate the NFB, a known inflammatory pathway. This contributes to maintaining skin homeostasis and makes mast cell tolerant to commensal bacteria. We found that DKK2, a specific protein secreted by DFs, modulates the huMC NF–B pathway, by increasing gene expression of TNFAIP3 (A20) and NFKBIA in huMCs. This modulation results in a decreased inflammatory response to commensal bacteria. In this proposal, we will clarify the mechanisms of DF - MC signaling, which induces a MC skin tolerant phenotype. This is an important mechanism for skin inflammation and atopic dermatitis (AD) in particular. We will present preliminary data that show that in AD, DFs fail to maintain human MC (huMC) tolerance to commensal bacteria which allows huMC to release proinflammatory cytokines. The idea that inflammatory diseases develop because MC tolerance is broken represents a shift in science paradigm. This work will identify the mechanisms underlying the roles of huMCs in building and breaking tolerance to the skin’s rich environment. We propose the followings: 1. To determine whether TNFAIP3 (A20) and NFKBIA in human MCs are required for preventing proinflammatory interleukin responses (tolerance) to commensal supernatant. In Aim 1 of this proposal, we will use a variety of structural, biophysical, biochemical, and functional assays to determine how dermal MCs collaborate with DFs. More specifically, we will analyze the MC expression of the NF–B related genes, TNFAIP3 (A20) and NFKBIA, as well as receptors related to the innate immune system in dermal huMCs. 2. To confirm that MC tolerance can be induced by DKK2 from DFs In Aim 2, we will determine whether DF DKK2 is required for inducing huMC tolerance to commensal supernatant and whether different DF sub-populations vary in their ability to induce tolerance in huMCs. 3. To confirm that DF-induced MC tolerance to commensal bacteria is critical for suppressing human skin inflammation. In Aim 3 of this proposal we will look at the consequences of the failure of huMCs to maintain tolerance and their role in skin inflammation, specifically in Atopic Dermatitis skin.

摘要我们已经证明，进入皮肤的肥大细胞通过与真皮接触而改变表型。成纤维细胞（DF）。在皮肤中，肥大细胞（MC）下调其TLR 2并增加基因表达下调NF κ B B，一种已知的炎症途径。这有助于维持皮肤的稳态并使肥大细胞对肠道细菌耐受。我们发现DKK 2，一种由DF分泌的特异性蛋白，调节huMC NF-κ B B通路，通过增加TNF α IP 3（A20）和NF κ BIA的基因表达， huMC。这种调节导致对肠道细菌的炎症反应降低。在这建议，我们将阐明DF - MC信号传导的机制，该信号传导诱导MC皮肤耐受表型。这是皮肤炎症和特应性皮炎（AD）的重要机制。我们将介绍初步数据显示，在AD中，DF不能维持人MC（huMC）对肠道细菌的耐受性，这允许huMC释放促炎细胞因子。炎症性疾病发展的观点因为MC耐受性的打破代表了科学范式的转变。这项工作将确定在建立和破坏对皮肤丰富环境的耐受性中，huMCs的作用是潜在的。我们提出以下建议： 1.为了确定人类MC中的TNFAIP 3（A20）和NFKBIA是否是预防肿瘤所必需的，促炎性白细胞介素应答（耐受性）。目标1 建议，我们将使用各种结构，生物物理，生物化学和功能测定，确定真皮MC如何与DF合作。更具体地说，我们将分析MC表达式 NF-κ B B相关基因TNFAIP 3（A20）和NF κ BIA，以及与先天性免疫缺陷相关的受体。真皮huMCs中免疫系统。 2.证实DF的DKK 2可诱导MC耐受在目标2中，我们将确定DF DKK 2是否是诱导huMC对紫杉醇耐受所必需的。不同DF亚群诱导huMC耐受性的能力是否不同。 3.为了证实DF诱导的MC对肠道细菌的耐受性对于抑制人类皮肤炎症在本提案的目标3中，我们将研究huMC未能维持耐受性的后果以及它们在皮肤炎症中的作用，特别是在特应性皮炎皮肤中。