Epigenetic Regulation of Immunity in Alpha-1 Anti-trypsin Deficiency

Alpha-1 抗胰蛋白酶缺乏症免疫的表观遗传调控

基本信息

批准号：
8853045
负责人：
NABEEL HAMZEH
金额：
$ 39.39万
依托单位：
NATIONAL JEWISH HEALTH
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：
2015-09-16 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8853045
关键词：
Address Affect Alleles Alveolar Macrophages Alveolus Ancillary Study Bronchiectasis Cell physiology Cells Cessation of life ChIP-seq Chemotactic Factors Chromatin Chronic Obstructive Airway Disease Clinical Complex Coupled DNA Data Data Set Deacetylation Deficiency Diseases Detection Diagnosis Disease Elastases Elastin Environmental Exposure Enzymes Epigenetic Process Epithelial Cells Etiology Europe FDA approved Figs - dietary Gene Expression Gene Expression Profile Genes Genetic Transcription Genomics Genotype Goals Hepatocyte Hereditary Disease Heterozygote Histone Deacetylase Inhibitor Histones IL8 gene Immunity Individual Inflammation Inflammatory Inherited Lead Leukocyte Elastase Leukotriene B4 Liver Lung Lung diseases Lysine Maps Mediating Messenger RNA Methylation MicroRNAs Modification Molecular Molecular Profiling Monitor Other Genetics Panniculitis Parents Pathway interactions Patients Pattern Penetrance Pharmaceutical Preparations Play Polymers Post-Translational Protein Processing Precipitation Prevalence Problem Solving Production Protein Secretion Proteins Pulmonary Emphysema Pulmonary alveolar structure Regulation Replacement Therapy Research Role Sampling Sarcoidosis Serine Proteinase Inhibitors Smoking Source Symptoms Time Toxic effect Trypsin United States Vorinostat Whole Blood abstracting alpha 1-Antitrypsin alpha 1-Antitrypsin Deficiency base disease phenotype efficacy testing epigenetic regulation epigenomics gene function genome-wide histone modification macrophage meetings microbiome neutrophil next generation next generation sequencing novel strategies parent grant protein folding protein misfolding public health relevance success targeted treatment transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Alpha-1 antitrypsin deficiency (AATD) is an inherited genetic disorder that affects the level and function of alpha-1 antitrypsin (AAT). AAT is a serine protease inhibitor (PI) that is mainly produced in the liver but also in alveolar macrophages (AM) and pulmonary epithelial cells. Neutrophil elastase (NE), the primary target of AAT, degrades elastin in the pulmonary alveoli leading to parenchymal destruction and subsequent emphysema1. Instinctively, replacement therapy (augmentation therapy) with exogenous AAT to restore the level of AAT to above the protective threshold level, should solve the problem but there is controversy whether augmentation therapy is sufficiently efficacious. The goal of this study, an ancillary proposal to the Genomic Research in Alpha-1 Anti-trypsin Disease and Sarcoidosis (GRADS), is to define the changes in epigenetic alterations (histone modifications) in alveolar macrophages before and after augmentation therapy and their potential association with disease phenotype through comparison with healthy control samples. Our proposal is unique and complementary to the parent study as we are focusing on specific changes in epigenetic histone modifications in alveolar macrophages before and after augmentation therapy, whereas the parent grant will be assessing whole cell mRNA and miRNA expression. Our proposal is also time-sensitive as histone analysis requires freshly isolated cells and not stored DNA samples. We propose three aims to address our hypothesis that the environmentally influenced, variable pattern of histone modifications that can modulate AM mediated inflammation and can contribute to a variable clinical course of AATD, may also be influenced by or influence the molecular activity of AAT augmentation therapy. Using a novel approach that has not been undertaken in AATD but proven in other inflammatory pulmonary and non-pulmonary disorders, in Aim 1 we will compare the epigenomic signature of specific inflammation-associated histone post-translational modifications in AATD alveolar macrophages (AM) from PiZZ subjects before and after 6 months of AAT augmentation therapy via Chromatin Immuno-Precipitation coupled with next generation sequencing (ChIP-seq). In Aim 2 we will elucidate the AATD alveolar macrophage (AM) epigenetically regulated transcription profile via computational integration of AM RNA-seq gene expression data sets with ChIP-seq and in Aim 3, we will analyze the effects of histone modifying enzyme ex vivo treatment, such as HDACi treatment, on AATD associated AM gene expression and cell function. In all three aims, we incorporate healthy control samples to elucidate AATD- specific epigenetic and transcriptional signature. This project will elucidate the effect of augmentation therapy on the epigenetic signature of AM in AATD patients, enhancing our understanding of the immunomodulatory mechanisms regulating AATD and providing an epigenetic map for potentially targeted treatment.

描述（由申请人提供）：α-1 抗胰蛋白酶缺乏症（AATD）是一种影响 α-1 抗胰蛋白酶（AAT）水平和功能的遗传性疾病。AAT 是一种丝氨酸蛋白酶抑制剂（PI），主要产生于人体。肝脏中也存在肺泡巨噬细胞 (AM) 和肺上皮细胞 (NE)，AAT 的主要目标是降解肺泡中的弹性蛋白。实质上，用外源性 AAT 进行替代治疗（增强治疗）以将 AAT 水平恢复到保护阈值水平以上应该可以解决问题，但增强治疗是否足够有效仍存在争议。这项研究是 Alpha-1 抗胰蛋白酶疾病和结节病基因组研究 (GRADS) 的一项辅助提案，旨在定义表观遗传改变（组蛋白）的变化通过与健康对照样本进行比较，我们的建议是独特的，并且是对母研究的补充，因为我们专注于肺泡巨噬细胞在增强治疗之前和之后的表观遗传组蛋白修饰的具体变化。增强治疗后，而母基金将评估全细胞 mRNA 和 miRNA 表达，因为组蛋白分析需要新鲜分离的细胞而不是储存的 DNA 样本，我们提出三个目标来解决我们的假设，即环境影响。，多变的组蛋白修饰模式可以调节 AM 介导的炎症，并可能导致 AATD 的可变临床过程，也可能受到 AAT 增强疗法的分子活性的影响，该方法尚未在 AATD 中采用，但已在 AATD 中得到证实。其他炎症性肺部和非肺部疾病，在目标 1 中，我们将比较 PiZZ 受试者的 AATD 肺泡巨噬细胞 (AM) 前后特定炎症相关组蛋白翻译后修饰的表观基因组特征通过染色质免疫沉淀结合新一代测序 (ChIP-seq) 进行 6 个月的 AAT 增强治疗。在目标 2 中，我们将通过 AM RNA-seq 基因表达数据的计算整合来阐明 AATD 肺泡巨噬细胞 (AM) 表观遗传调控转录谱。使用 ChIP-seq 进行设置，在目标 3 中，我们将分析组蛋白修饰酶离体治疗（例如 HDACi 治疗）对 AATD 相关的影响在这三个目标中，我们结合了健康对照样本来阐明 AATD 特异性表观遗传和转录特征，该项目将阐明增强治疗对 AATD 患者中 AM 表观遗传特征的影响，从而增强我们对 AATD 患者的理解。调节 AATD 的免疫调节机制并为潜在的靶向治疗提供表观遗传图谱。