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Redor Pathways Regulating Nemeprotein Maturation in Asthma

Redor 通路调节哮喘中的 Neme 蛋白成熟

基本信息

批准号：
9232190
负责人：
DENNIS J STUEHR
金额：
$ 31.39万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-15 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9232190
关键词：
Address Adrenergic beta-Agonists Agonist Air Apoproteins Asthma Biological Models Bronchoconstriction Bronchodilation Bronchodilator Agents Cell Culture Techniques Cells Characteristics Coculture Techniques Data Defect Drug usage Environment Enzymes Epithelial Epithelial Cells FDA approved Glyceraldehyde-3-Phosphate Dehydrogenases Health Heme Hemeproteins Host Defense Human Individual Inflammation Liquid substance Lung Measures Mediating Metalloproteins Modeling Mus Muscle Cells Muscle function Muscle relaxants NOS1 gene NOS2A gene NOS3 gene Nitrates Nitric Oxide Nitric Oxide Synthase Nitrites Oxidation-Reduction Oxidoreductase Pathway interactions Patient Care Patients Pharmaceutical Preparations Pharmacology Play Production Prosthesis Pulmonary Hypertension Recycling Refractory Research Respiratory physiology Rest Role SKIL gene Slice Smooth Muscle Soluble Guanylate Cyclase Sulfhydryl Compounds System TXN gene Testing Translating Up-Regulation Vascular Smooth Muscle airway epithelium airway hyperresponsiveness airway inflammation asthmatic asthmatic airway base clinically relevant cytokine desensitization experimental study heme a improved in vivo macrophage member mouse model novel novel therapeutic intervention prevent programs receptor respiratory smooth muscle response restoration

项目摘要

ABSTRACT - PROJECT 3 Metalloproteins that contain a heme prosthetic group (hemeproteins) are essential to lung functions, including airway host defense and inflammation [inducible nitric oxide (NO) synthase (iNOS)], and bronchomotor tone [soluble guanylate cyclase (sGC)]. We recently discovered that NO inhibits heme insertion into apo-proteins by the S-nitrosyation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which functions in heme transport and insertion. Recycling GAPDH is dependent on cellular redox and S-denitrosylase enzymes, i.e. GSNO reductase (GSNOR) or thioredoxin 1 (Trx1). These exciting findings and longstanding interactions with Program members in the study of asthma over the years made it a natural step to investigate whether the high- levels of NO in the asthmatic airway blocks hemeprotein maturation. Our preliminary results show that asthmatic airway epithelium escapes NO-mediated inhibition of heme insertion by upregulation of denitrosylase pathways, enabling the expression of active iNOS, but that airway smooth muscle cells are overwhelmed by NO at the levels produced in the asthmatic airway, with consequent loss of heme-replete sGC. New preliminary data generated in murine models of asthma and in the human precision cut lung slice model suggest that heme-independent sGC-activators are strikingly effective bronchodilators. Thus, we will test the hypothesis that thiol denitrosylase systems enable continuous airway epithelial NO production by iNOS in asthma by restoration of hemeprotein maturation, but that the NO overwhelms smooth muscle denitrosylase systems, compromising maturation & function of the sGC in smooth muscle, which results in bronchoconstriction and airway hyper-reactivity. We plan concurrent mechanistic studies and studies of the bronchodilator response to novel pharmacologic sGC agonists in (i) primary airway smooth muscle cells from healthy and asthmatic airways, (ii) precision cut human lung slice model and (iii) mouse models of asthma using genetically modified mice (including NOS1,2,&3 -/-, GSNOR-/- and smooth muscle specific sGC-/-). Also, we will study hemeprotein maturation in airway epithelial cells freshly obtained from healthy individuals and asthmatics with low or high FENO to help verify clinical relevance and potentially endotype sGC-agonist responders. sGC agonists will be tested in order to translate the discoveries to patient care soon. This research will provide the first information on hemeprotein maturation in healthy and asthmatic airway, and test connections between dysregulation of hemeprotein maturation and the bronchoconstriction and inflammation characteristic of asthma.

摘要-项目3