Screening for inhibitors of allergen-associated airway smooth muscle contraction

筛选过敏原相关气道平滑肌收缩抑制剂

基本信息

批准号：
10176398
负责人：
RAMASWAMY KRISHNAN
金额：
$ 21.88万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176398
关键词：
Adrenal Cortex Hormones Affinity AlamarBlue Allergens Allergic inflammation Animals Antifungal Agents Aspergillus fumigatus Asthma Biological Assay Biological Sciences Bronchoconstriction Bronchodilator Agents Cell Survival Cytoskeleton Data Dinoprostone Disease Dose Evaluation Extracellular Matrix Focal Adhesions Gene Expression Generations Human Hypersensitivity IgE Inflammatory Inhalation Lead Life Lung Measurement Mediating Mediator of activation protein Molds Mucous Membrane Mus Muscle Contraction Mycoses N-Cadherin Patients Peptide Hydrolases Production Safety Scheme Serine Protease Serine Proteinase Inhibitors Signal Pathway Slice Smooth Muscle Myocytes Stress Fibers Submucosa Symptoms Testing Therapeutic Toxic effect Validation aggressive therapy airway hyperresponsiveness alkalinity anti-IgE asthmatic asthmatic airway smooth muscle asthmatic patient attenuation base comparative constriction cytokine cytotoxicity design drug candidate druggable target experience follow-up fungus high throughput screening in vivo inhibitor/antagonist insight novel omalizumab precision medicine protein expression public health relevance respiratory smooth muscle screening small molecular inhibitor small molecule inhibitor therapeutic target

项目摘要

PROJECT SUMMARY Despite aggressive treatment with high-dose inhaled corticosteroids plus bronchodilators, approximately 5-10% of people with asthma (15-30 million) experience severe and life-threatening symptoms of bronchoconstriction. Nearly one-half of these severe asthma patients are also “sensitized” (i.e. have IgE mediated allergy) to common molds such as Aspergillus fumigatus (Af). This condition has now been recognized as a distinct entity and designated fungal asthma (FA). Unfortunately, current therapies for FA—antifungals and/or omalizumab (anti- IgE)—have not proven to be efficacious in the long-term. By studying Af-induced bronchoconstriction in mice and people with asthma, our team has discovered a novel, direct, and druggable target in FA—the Af allergen-derived serine protease, alkaline protease 1 (Alp1). Alp1 promotes the defining symptom of FA—bronchoconstriction—by inducing airway smooth muscle (ASM) contraction, through mechanisms that appear to be independent of allergic inflammation. In this application, we will pursue the hypothesis that inhibitors of Alp1-induced human ASM contraction can be discovered by high throughput screening (HTS). In aim 1, we will use HTS to identify small molecular inhibitors of Alp1 protease. In aim 2, we will examine the effects of FA pathobiology on the efficacy of Alp1-inhibitor therapy. In aim 3, we will determine mechanism and examine significance for Alp1-inhibitor therapy. We expect our approach to identify novel anti-FA drug candidates, and in doing so, offer substantial insight into both ASM-intrinsic and allergen protease dependent mechanisms of bronchoconstriction.

项目摘要尽管用高剂量遗传性皮质类固醇加上支气管扩张剂进行了积极的治疗，但约为5-10％哮喘（15-30亿）患者经历了严重的危害生命的支气管收缩症状。这些严重的哮喘患者中有将近一半也“敏感”（即对IgE介导的过敏）对常见烟曲霉（AF）等霉菌。现在，这种情况已被认为是一个独特的实体，指定的真菌哮喘（FA）。不幸的是，FA的当前疗法 - 抗直导和/或Omalizumab（抗 IGE） - 从长远来看，未被证明是有效的。通过研究小鼠和患有哮喘患者的AF诱导的支气管收缩，我们的团队发现了一部小说， FA中的直接且可吸毒的靶标 - AF过敏原衍生的丝氨酸蛋白酶，酒精蛋白酶1（ALP1）。通过诱导的气道平滑肌（ASM）来促进FA的定义症状（支核收缩）收缩，通过似乎独立于过敏注射的机制。在此应用程序中，我们将提出以下假设：ALP1诱导的人ASM收缩的抑制剂可以通过高吞吐量筛选（HTS）。在AIM 1中，我们将使用HTS鉴定ALP1蛋白酶的小分子抑制剂。在 AIM 2，我们将研究FA病理生物学对ALP1抑制剂疗法有效性的影响。在AIM 3中，我们将确定ALP1抑制剂疗法的机制和检查显着性。我们希望我们的方法可以识别新颖的抗FA候选药物，并在此过程中对ASM Intrinsic和过敏原提供了实质性的见解支气管收缩的蛋白酶依赖性机制。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multiscale stiffness of human emphysematous precision cut lung slices.

DOI：
10.1126/sciadv.adf2535
发表时间：
2023-05-19
期刊：
SCIENCE ADVANCES
影响因子：
13.6
作者：
Kim, Jae Hun;Schaible, Niccole;Hall, Joseph K.;Bartolak-Suki, Erzsebet;Deng, Yuqing;Herrmann, Jacob;Sonnenberg, Adam;Behrsing, Holger P.;Lutchen, Kenneth R.;Krishnan, Ramaswamy;Suki, Bela
通讯作者：
Suki, Bela

CD38 plays an age-related role in cholinergic deregulation of airway smooth muscle contractility.