Small Heat Shock Proteins in Human Airway Smooth Muscle Tone and Pathophysiology

人呼吸道平滑肌张力和病理生理学中的小热休克蛋白

基本信息

批准号：
8903540
负责人：
Padmini Komalavilas
金额：
$ 29.25万
依托单位：
MIDDLE TENNESSEE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903540
关键词：
Accident and Emergency department Accounting Acids Actins Acute Adenylate Cyclase Adjuvant Adrenergic Agonists Adrenergic Receptor Adverse effects Affect Agonist Alanine Amino Acids Anti-Inflammatory Agents Asthma Behavior Binding Bronchial Spasm Bronchodilator Agents Bypass Canis familiaris Cattle Cell physiology Cells Chronic Clinical Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic Nucleotides Data Event F-Actin Family suidae Figs - dietary Functional disorder Gene Silencing Genetic Polymorphism Genotype Health Heat shock proteins Heat-Shock Response Hospitalization Human Inflammation Investigation Mediating Membrane Methods Microfilaments Modeling Molecular Molecular Target Morbidity - disease rate Mus Muscle Tonus Muscle relaxation phase Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Phosphopeptides Phosphorylation Physiological Play Polymers Population Prevalence Proline Protein Kinase Proteins Pyroglyphidae Recombinants Refractory Regulation Relaxation Resistance Role Scaffolding Protein Scanning Small Interfering RNA Smooth Muscle Myocytes Therapeutic Translating Visit Work actin depolymerizing proteins arginylarginine base beta-2 Adrenergic Receptors cofilin constriction cost depolymerization desensitization drug candidate heat-shock protein pp3 in vivo mimetics mortality nanoparticle novel novel strategies peptide analog receptor respiratory smooth muscle response

项目摘要

DESCRIPTION (provided by applicant): Severe acute asthma, defined as asthma that is refractory to current anti-inflammatory agents and bronchodilators, accounts for an estimated two-million emergency department visits annually. beta 2-adrenergic receptor agonists (beta-agonists) are widely used for the treatment of bronchospasm associated with acute asthma attacks, however, some patients develop refractory responses to long term usage of beta-agonists, and it also causes adverse effects in patients with a genetic polymorphism (Arg/Arg genotype, about a sixth of the US population) in the adrenergic receptor creating a need for additional therapeutics for managing asthma. Beta-agonists mediate their effect primarily through activation of beta 2 -adrenergic receptor-adenylate cyclase pathway, but the molecular mechanisms underlying the action of beta-agonists are still not completely defined. Recently, we and others have demonstrated that beta-agonist induced airway relaxation is associated with increases in the phosphorylation of HSP20 and that transducible phosphopeptide mimetics of HSP20 protein as well as recombinant HSP20 protein promote actin depolymerization and relaxation. This proposal will examine how manipulating the expression and phosphorylation of HSP20 affect human airway smooth muscle tone and characterize the molecular events of HSP20- and the phospho HSP20 peptide -mediated actin filament regulation and relaxation. The hypothesis of this investigation is that cyclic nucleotide induced relaxation of human airway smooth muscle is associated with phosphorylation changes of HSP20 and that phospho-peptide mimetics of the small heat shock proteins will circumvent the problems associated with hypo-responsiveness of the beta-agonists in the management of airway constriction. The aims of this proposal are to 1): Determine if manipulating HSP20 levels affect relaxation of human airway smooth muscle tone through actin cytoskeletal regulation. (2). Optimize the-p-P20 peptides to enhance the bioactivity of the peptides ex vivo using human ASM. 3): Determine the effects of the phospho-HSP20 peptide in vivo in a murine asthma model. These studies will further our understanding of the mechanisms by which HSP20 induces changes in cellular physiology and relaxation of human airway smooth muscle and develop a peptide therapeutic that can circumvent the problems associated with beta-agonists to enhance airway smooth muscle relaxation thus reducing the morbidity, mortality, and costs associated with managing asthma.

描述（由申请人提供）：严重急性哮喘（定义为当前抗炎药和支气管扩张剂难以治疗的哮喘）每年估计有 200 万人次到急诊室就诊。 β2-肾上腺素能受体激动剂（β-激动剂）广泛用于治疗与急性哮喘发作相关的支气管痉挛，然而，一些患者对长期使用β-激动剂会出现难治性反应，并且还会对以下患者造成不良反应：肾上腺素受体的基因多态性（Arg/Arg 基因型，约占美国人口的六分之一）导致需要额外的治疗方法来控制哮喘。 β-激动剂主要通过激活β2-肾上腺素能受体-腺苷酸环化酶途径介导其作用，但β-激动剂作用的分子机制尚未完全明确。最近，我们和其他人证明β-激动剂诱导的气道松弛与HSP20磷酸化的增加有关，并且HSP20蛋白的可转导磷酸肽模拟物以及重组HSP20蛋白促进肌动蛋白解聚和松弛。该提案将研究操纵 HSP20 的表达和磷酸化如何影响人气道平滑肌张力，并表征 HSP20 和磷酸化 HSP20 肽介导的肌动蛋白丝调节和松弛的分子事件。这项研究的假设是，环核苷酸诱导的人气道平滑肌松弛与 HSP20 的磷酸化变化有关，并且小热休克蛋白的磷酸肽模拟物将避免与 β 激动剂低反应性相关的问题。气道收缩的管理。该提案的目的是 1)：确定操纵 HSP20 水平是否通过肌动蛋白细胞骨架调节影响人气道平滑肌张力的松弛。（2）。使用人 ASM 优化 -p-P20 肽以增强肽的离体生物活性。 3)：确定磷酸-HSP20肽在小鼠哮喘模型中的体内作用。这些研究将进一步加深我们对 HSP20 诱导细胞生理学变化和人气道平滑肌松弛的机制的理解，并开发一种肽治疗剂，可以规避与 β-激动剂相关的问题，从而增强气道平滑肌松弛，从而降低发病率。死亡率以及与治疗哮喘相关的费用。