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：
9509513
负责人：
NABEEL HAMZEH
金额：
$ 39.43万
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 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9509513
关键词：
Address Affect Alleles Alveolar Macrophages Ancillary Study Bronchiectasis Cell physiology Cells Cessation of life ChIP-seq Chemotactic Factors 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 Expression Profiling FDA approved Gene Expression Gene Expression Profile Genes Genetic Transcription Genomics Genotype Goals HDAC4 gene Hepatocyte Hereditary Disease Heterozygote Histone Deacetylase Inhibitor Histones IL8 gene Immunity Impairment Individual Inflammation Inflammatory Instinct Lead Leukocyte Elastase Leukotriene B4 Liver Lung Lysine Maps Mediating Messenger RNA Methylation MicroRNAs Modification Molecular Monitor Other Genetics PARP9 gene Panniculitis Parents Pathway interactions Patients Pattern Penetrance Pharmaceutical Preparations Play Polymers Post-Translational Protein Processing 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 alpha 1-Antitrypsin alpha 1-Antitrypsin Deficiency base chromatin immunoprecipitation disease phenotype efficacy testing epigenetic regulation epigenomics gene function genome-wide histone modification immunoregulation lung microbiome macrophage neutrophil next generation next generation sequencing novel strategies parent grant protein folding protein misfolding public health relevance rare condition success targeted treatment transcriptome 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（由应用程序提供）：Alpha-1抗胰蛋白酶缺乏症（AATD）是一种遗传性遗传疾病，影响α-1抗胰蛋白酶（AAT）的水平和功能。 AAT是一种序列蛋白抑制剂（PI），主要是在肝脏中产生的，也是肺泡巨噬细胞（AM）和肺上皮细胞。 AAT的主要靶标，中性粒细胞弹性酶（NE）在肺肺泡中降解弹性蛋白，从而导致副群破坏和随后的肺气肿1。本能地，用外源性AAT替换疗法（增强疗法）可以解决该问题，以恢复AAT的水平至高于受保护的阈值水平，但是存在争议是否足够有效。这项研究的目的是对α-1抗肌蛋白疾病和结节症（GRADS）的基因组研究的辅助提案，是为了确定在增强治疗前后的肺泡巨噬细胞中表观遗传学改变（组蛋白修饰）的变化，并在增强疗法及其与健康对照样品相比与疾病表型相比。我们的建议在父母研究中是独一无二的，并且是在增强治疗前后的肺泡巨噬细胞中表观遗传组蛋白修饰的特定变化时的独特性和完整的，而父母赠款将评估整个细胞mRNA和miRNA表达。我们的建议也对时间敏感，因为组蛋白分析需要新鲜分离的细胞而不是存储的DNA样品。我们提出三个旨在解决我们的假设，即受环境影响的，可变的组蛋白修饰模式可以调节AM介导的感染并可能有助于AATD的可变临床过程，也可能受到AAT增强治疗的分子活性的影响或影响。 Using a novel approach that has not been undertaken AATD but proved 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生成测序（CHIP-SEQ）。在AIM 2中，我们将通过AM RNA-SEQ基因表达数据集的AM RNA-SEQ基因表达数据集的计算整合，在AIM 3中，我们将分析组蛋白修饰的酶治疗的酶，例如HDACI治疗，例如HDACI治疗AMD AM基因，我们将分析组蛋白修饰的酶对AT A. ATD相关的Cynee AM Genee Am gene Enee and compants and AIM 3，在AIM 2中，我们将通过AM RNA-Seq基因表达数据集的计算整合来阐明AATD肺泡巨噬细胞（AM）。在所有三个目标中，我们都融合了健康的对照样品，以阐明AATD特异性表观遗传和转录特征。该项目将阐明增强疗法对AATD患者AM表观遗传学特征的影响，从而增强我们对治疗AATD的免疫调节机制的理解，并为潜在靶向治疗提供表观遗传学图。