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Force phenotyping of airway smooth muscle cells to develop novel asthma therapies

强制气道平滑肌细胞表型分析以开发新型哮喘疗法

基本信息

批准号：
9299599
负责人：
Dino Di Carlo
金额：
$ 20.91万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9299599
关键词：
Actomyosin Acute Address Adrenal Cortex Hormones Affect Agonist Animal Model Asthma Biological Assay Breathing Bronchoconstriction Bronchodilator Agents Calcium Cardiac Myocytes Cells Chemicals Clinical Cyclic AMP Data Development Disease Drug Targeting Effectiveness Emergency Situation Epigenetic Process Extracellular Matrix FDA approved Fibroblasts Future Generations Genomics Human Immunofluorescence Immunologic Inflammation Inflammation Mediators Inhalators Lead Legal patent Libraries Link Lung Measurement Measures Methods Molecular Monitor Muscle Cells Muscle Contraction Muscle Tonus Muscle relaxation phase Myosin Light Chain Kinase Natural Products Opsonin Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Phenotype Play Potassium Channel Preclinical Drug Evaluation Relaxation Respiratory physiology Role Second Messenger Systems Signal Transduction Slice Smooth Muscle Specificity Speed Staining method Stains Surface System Techniques Testing Time Tissue Model Tissues Vascular Smooth Muscle airway hyperresponsiveness asthma inhaler asthmatic patient base beta-2 Adrenergic Receptors cell type constriction design drug discovery experimental study high throughput screening inhibitor/antagonist macrophage mechanical behavior molecular phenotype mortality new therapeutic target novel novel therapeutics prevent release of sequestered calcium ion into cytoplasm respiratory smooth muscle response screening tool

项目摘要

ABSTRACT Asthma is currently treated with drugs that target inflammation (e.g. corticosteroids) and the subsequent bronchoconstriction (β2 adrenergic receptor agonists) that leads to airway narrowing. Although there are a variety of mechanisms to inhibit cell force generation and contraction, short- and long-acting bronchodilators operate through a single mechanism of action, which has negative consequences, since adaptation to a long-acting beta agonist leads to reduced efficacy of short-acting beta agonist “rescue inhalers.” There is a need for new drugs that target airway smooth muscle contractility through orthogonal pathways to the beta agonists. However, there are no current methods to perform high-throughput screens targeting cell force generation. We have developed a microtechnology-based high-throughput screening approach to characterize cellular force generation at the single-cell level. We hypothesize that new drugs that interfere with airway smooth muscle cell contractility can be found that act through separate pathways and lead to new treatment options for asthma patients. In Aim 1 we will conduct a high-throughput screen to identify compounds that relax contraction in airway smooth muscle cells. We will validate hit compounds in a tissue model - precision cut lung slices. We also anticipate that selective inhibitors of airway smooth muscle contraction can be developed by counter-screening against other contractile cells. Our platform allows for combined measurement of immunofluorescence, calcium levels, and contractile phenotypes for single cells. In Aim 2 we will use this capability to address whether calcium mobilization is increasing and sufficient to evoke HASM cell shortening by contractile agonists. Molecular inputs that modulate smooth muscle actomyosin cross-bridge cycling and the strength of contraction remain less understood given the larger variety of inputs that control smooth muscle tone. Also, we will use this platform to identify new surface markers associated with hyper-responsive contractile phenotypes highlighting potential key ASM subpopulations involved in disease. Such surface markers would also assist in designing cell-targeted anti-contractility drugs for asthma in the future.

摘要