Identification of Candidate Genes for Specific Immune Responsiveness to Cockroach

蟑螂特异性免疫反应候选基因的鉴定

基本信息

批准号：
8142927
负责人：
Kathleen C Barnes
金额：
$ 20.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8142927
关键词：
African African American Allergens Allergic Disease Antigen-Presenting Cells Antigens Asthma CCL8 gene CD14 gene CD4 Positive T Lymphocytes Candidate Disease Gene Cell Maturation Cell physiology Clinical Immunology Cluster Analysis Coculture Techniques Data Data Set Databases Dendritic Cells Development Dictyoptera Endotoxins Ethnic Origin Exposure to Extrinsic asthma Foundations Functional disorder Future Gene Cluster Gene Expression Gene Expression Profiling Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genome Genomics Human Hypersensitivity Immune Immune response Immunologics Individual Interleukin-10 Interleukin-12 Interleukin-13 Interleukin-6 Lead Ligands Mediating Minority Groups Modeling Molecular Genetics Molecular Profiling Morbidity - disease rate Myelogenous Pathway interactions Patients Pattern Population Positioning Attribute Predisposition Production Public Health Receptor Signaling Regulatory Pathway Resources Rest Risk Risk Factors Role S100A8 gene Sample Size Sampling Signal Pathway T-Cell Proliferation T-Lymphocyte TNF gene Tissue-Specific Gene Expression Toll-like receptors Tumor Necrosis Factor-alpha Underrepresented Minority United States National Institutes of Health airborne allergen allergic response base cockroach allergen cytokine disorder risk epidemiology study ethnic minority population genetic association genetic epidemiology genome wide association study human TNF protein human subject public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Sensitization and exposure to cockroach allergen is one of the strongest predictors of asthma morbidity, especially among African Americans, yet its underlying mechanisms and the genetic etiology for allergenicity specific to cockroach antigen are largely unknown. We hypothesize that there are distinct genes controlling susceptibility to cockroach allergen which subsequently contribute to the added risk of asthma. In particular, cockroach antigen may confer susceptibility to dendritic cell (DC) dysfunction and lead to a polarized Th2 response, a pattern which we hypothesize is (1) unique among cockroach sensitized asthmatic individuals compared to atopic asthma subjects without cockroach, and (2) distinct from a specific immune response to other common aeroallergens. Our hypothesis is based on the following observations in preliminary studies: (1) cockroach allergen is capable of activating DCs, leading to a Th2-type cytokine production, (2) using high- throughput expression profiling, we have already observed specific "transcriptional signatures" in ex vivo plasmacytoid DCs (pDCs) and CD4+ T cells from cockroach-sensitized patients in response to cockroach allergen; and (3) Initial analyses from two ongoing genome-wide association study (GWAS) on asthma in the African American population provided significant evidence for association between cockroach sensitization and several loci. In this application, we will expand our previous study to include a sufficiently powered sample size of human subjects, focus on 2 major purified human DC subtypes [pDCs and myeloid DCs (mDCs)] as opposed to previous cocultured pDCs and CD4+ T cells, and control for important confounders (endotoxin contamination, sensitization to irrelevant allergens, and the potential impact of ethnicity). Our specific aims are: (1) To characterize the specific effects of cockroach extract on DC functions in well-characterized atopic asthma subjects with and without cockroach sensitization by evaluating DC maturation, cytokine production and APC function in T cell polarization ex vivo; and (2) To utilize high-throughput gene expression profiling of isolated DCs for prioritization of candidate genes for cockroach sensitization. Given our findings from this proposal, combined with the immediate availability of raw genetic data from 2 datasets of African ancestry as part of an ongoing GWAS, we believe we are exceptionally positioned to identify candidate genes responsible for specific immune responsiveness to cockroach allergen. These candidates will provide the foundation for a future, NIH-supported application focused on genetic association studies in populations of African descent, and studies on interrogating the role of relevant polymorphisms and risk of cockroach sensitization. Ultimately, these collective studies will result in the characterization of the molecular and genetic mechanisms associated with cockroach-induced Th2-mediated immune responses and allergic diseases, including asthma, with a specific focus on an ethnic minority population (e.g., African Americans) at greatest risk of disease, and lead to better targets of therapy. PUBLIC HEALTH RELEVANCE: Sensitization and exposure to cockroach allergen is one of the strongest risk factors of asthma morbidity and has a strong genetic basis. We will study the effect of cockroach allergen exposure on dendritic cell function and identify candidate genes for cockroach-induced specific immune response using whole genome expression studies. This will generate a reliable list of candidate genes for future studies in populations of African descent.

描述（由申请人提供）：对蟑螂过敏原的过敏和接触是哮喘发病的最强预测因素之一，尤其是在非裔美国人中，但其潜在机制和蟑螂抗原特异性过敏的遗传病因在很大程度上尚不清楚。我们假设有不同的基因控制对蟑螂过敏原的易感性，从而导致哮喘风险增加。特别是，蟑螂抗原可能会导致树突状细胞（DC）功能障碍的易感性，并导致极化的 Th2 反应，我们假设这种模式是（1）与没有蟑螂的特应性哮喘受试者相比，蟑螂过敏的哮喘个体是独特的，（2）与对其他常见空气过敏原的特异性免疫反应不同。我们的假设基于初步研究中的以下观察结果：（1）蟑螂过敏原能够激活 DC，导致 Th2 型细胞因子的产生，（2）使用高通量表达谱，我们已经观察到特定的“转录特征”来自蟑螂过敏患者的离体浆细胞样 DC (pDC) 和 CD4+ T 细胞对蟑螂过敏原的反应； (3) 两项正在进行的非裔美国人哮喘全基因组关联研究 (GWAS) 的初步分析为蟑螂致敏与多个位点之间的关联提供了重要证据。在此应用中，我们将扩大之前的研究范围，纳入足够有力的人类受试者样本量，重点关注 2 种主要的纯化人类 DC 亚型 [pDC 和髓样 DC (mDC)]，而不是之前共培养的 pDC 和 CD4+ T 细胞，以及控制重要的混杂因素（内毒素污染、对不相关过敏原的敏感性以及种族的潜在影响）。我们的具体目标是：（1）通过评估离体 T 细胞极化中 DC 的成熟、细胞因子的产生和 APC 功能，来表征蟑螂提取物对有或没有蟑螂致敏的特应性哮喘受试者的 DC 功能的具体影响； (2) 利用分离树突状细胞的高通量基因表达谱来确定蟑螂致敏候选基因的优先顺序。鉴于我们在这项提案中的发现，再加上作为正在进行的 GWAS 的一部分，来自非洲血统的两个数据集的原始遗传数据的即时可用，我们相信我们处于特殊地位，可以识别负责对蟑螂过敏原的特异性免疫反应的候选基因。这些候选者将为美国国立卫生研究院支持的未来应用奠定基础，该应用的重点是非洲人后裔群体的遗传关联研究，以及探讨相关多态性的作用和蟑螂致敏风险的研究。最终，这些集体研究将确定与蟑螂诱导的 Th2 介导的免疫反应和过敏性疾病（包括哮喘）相关的分子和遗传机制的特征，最多特别关注少数族裔人群（例如非裔美国人）疾病风险，并导致更好的治疗目标。公共卫生相关性：对蟑螂过敏原的过敏和接触是哮喘发病的最强危险因素之一，并且具有很强的遗传基础。我们将研究蟑螂过敏原暴露对树突状细胞功能的影响，并利用全基因组表达研究鉴定蟑螂诱导的特异性免疫反应的候选基因。这将为未来对非洲人后裔的研究产生可靠的候选基因列表。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic variants in mannose receptor gene (MRC1) confer susceptibility to increased risk of sarcoidosis.

甘露糖受体基因 (MRC1) 的遗传变异导致结节病风险增加。

DOI：
发表时间：
2010
期刊：
影响因子：
0
作者：
Hattori, Takeshi;Konno, Satoshi;Takahashi, Ayumu;Isada, Akira;Shimizu, Kaoruko;Shimizu, Kenichi;Taniguchi, Natsuko;Gao, Peisong;Yamaguchi, Etsuro;Hizawa, Nobuyuki;Huang, Shau;Nishimura, Masaharu
通讯作者：
Nishimura, Masaharu

Macrophage polarization and allergic asthma.

巨噬细胞极化和过敏性哮喘。

DOI：
发表时间：
2018-01
期刊：
影响因子：
0
作者：
Saradna, Arjun;Do, Danh C;Kumar, Shruthi;Fu, Qing;Gao, Peisong
通讯作者：
Gao, Peisong

Functional effects of TGF-β1 on mesenchymal stem cell mobilization in cockroach allergen-induced asthma.

TGF-β1 对蟑螂过敏原诱发哮喘中间充质干细胞动员的功能影响。

DOI：
发表时间：
2014-05-15
期刊：
影响因子：
0
作者：
Gao, Peisong;Zhou, Yufeng;Xian, Lingling;Li, Changjun;Xu, Ting;Plunkett, Beverly;Huang, Shau;Wan, Mei;Cao, Xu
通讯作者：
Cao, Xu

Aryl hydrocarbon receptor (AhR) modulates cockroach allergen-induced immune responses through active TGFβ1 release.

芳基碳氢化合物受体 (AhR) 通过主动 TGFβ1 释放调节蟑螂过敏原诱导的免疫反应。