Gelsolin modulation of airway hyperresponsiveness and inflammation

凝溶胶蛋白调节气道高反应性和炎症

基本信息

批准号：
10208940
负责人：
Maya Mikami
金额：
$ 15.9万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208940
关键词：
Actins Acute Address Adoptive Transfer Agonist Allergens Allergic Alveolar Macrophages Antigen Presentation Area Asthma Attenuated Binding Biology Calcium Calcium Signaling Cell physiology Cells Cellular biology Characteristics Chemotaxis Chronic Cleaved cell Clinical Complement Complex Cytometry Cytoplasm Cytoskeleton Data Development Dichloromethylene Diphosphonate Exhibits Extramural Activities Foundations Functional disorder G Actin Gelsolin Generations Human Immune Immune Targeting Immunology Impairment In Vitro Inflammation Inhalation Inositol Interleukin-17 Interleukin-4 Ion Channel Laboratories Length Ligands Literature Lung Lung Inflammation Lung diseases M2 protein Magnetism Measures Mechanics Mediating Medical Mentors Microfilaments Mus Muscle Contraction Muscle relaxation phase Nebulizer Pathologic Pathway interactions Patients Peptide Fragments Peptides Peripheral Phagocytosis Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipase Physicians Physiology Play Prevalence Process Proteins Public Health Relaxation Research Research Training Resistance Role Scientist Slice Smooth Muscle Smooth Muscle Myocytes Stains Symptoms T-Cell Activation Taste Buds Techniques Therapeutic Training Wild Type Mouse actin capping protein actin depolymerizing proteins airway hyperresponsiveness airway inflammation asthmatic attenuation career career development cell motility cytokine first responder immunoregulation improved in vivo injured airway lentiviral-mediated lung development macrophage migration neutrophil novel novel therapeutics overexpression protein function receptor respiratory smooth muscle response tripolyphosphate

项目摘要

Project Summary/Abstract There is emerging evidence in the literature that diverse classes of novel ligands for asthma can acutely relax airway smooth muscle (ASM) despite a transient increase in intracellular calcium concentrations, which has classically been associated with contraction, not relaxation. Gelsolin is a calcium-activated actin severing protein that depolymerizes the actin cytoskeleton leading to ASM relaxation. Thus, activation of gelsolin by transient intracellular calcium increases may be the unifying mechanism that would account for ASM relaxation by these diverse ligands. In this proposal, we present exciting preliminary data demonstrating that mice genetically lacking gelsolin exhibit impaired ASM relaxation in vitro, ex vivo and in vivo. In addition to severing actin, intracellular gelsolin has a binding domain for phosphatidylinositol 4,5 bisphosphate (PIP2), which is the substrate for phospholipase Cβ synthesis of inositol triphosphate (IP3), the critical regulator of smooth muscle calcium release and contraction. We will further demonstrate that controlling intracellular gelsolin expression and activation is a therapeutic strategy for ASM cell relaxation using lentiviral-mediated overexpression of full length gelsolin and by the introduction of a short gelsolin peptide containing the binding domain for PIP2, which would selectively impair Gq-mediated increases in intracellular calcium. This proposal also demonstrate gelsolin’s role in the development of lung inflammation, which is another key pathological characteristic in asthma. We propose to demonstrate that pulmonary macrophages, in which gelsolin is abundantly expressed, can be a target for immune modulation in allergic lung inflammation. We will demonstrate that local delivery of a peptide fragment of gelsolin decreases airway smooth muscle contraction and allergic lung inflammation. A mentoring committee composed of successful scientists and physician-scientists will provide scientific expertise in each aspect of the research plan including ion channel physiology, calcium signaling, Th2 lung inflammation, lung immunology and macrophage biology. A comprehensive plan of intramural and extramural coursework and training complemented by additional collaborators with expertise in precision cut lung slices and magnetic twisting cell cytometry will expand the research training and career development. The research topic is ideal for a path to independent research in areas of airway smooth muscle pathophysiology and lung immune cell biology in allergic lung inflammation. Taken as a whole, this K08 proposal outlines a robust pathway to scientific independence and the foundation of a successful and sustained career as a physician-scientist.

项目概要/摘要文献中有新的证据表明，不同类别的新型哮喘配体可以急性尽管细胞内钙浓度短暂增加，但仍能放松气道平滑肌（ASM），这凝溶胶蛋白通常与收缩有关，而不是与松弛有关。解聚肌动蛋白细胞骨架导致 ASM 松弛的蛋白质，从而激活凝溶胶蛋白。短暂的细胞内钙增加可能是解释 ASM 松弛的统一机制在这个提案中，我们提出了令人兴奋的初步数据，证明小鼠。遗传性缺乏凝溶胶蛋白除了导致ASM松弛外，在体外、离体和体内也表现出受损。肌动蛋白，细胞内凝溶胶蛋白，具有磷脂酰肌醇 4,5 二磷酸 (PIP2) 的结合域，这是磷脂酶 Cβ 合成肌醇三磷酸 (IP3) 的底物，平滑肌的关键调节剂我们将进一步证明控制细胞内凝溶胶蛋白的表达和收缩。激活是一种利用慢病毒介导的全长过表达来松弛 ASM 细胞的治疗策略凝溶胶蛋白并通过引入含有 PIP2 结合域的短凝溶胶蛋白肽，这将选择性地损害 Gq 介导的细胞内钙的增加。该提议还证明了凝溶胶蛋白的作用。我们认为，肺部炎症的发展是哮喘的另一个关键病理特征。证明凝溶胶蛋白大量表达的肺巨噬细胞可以成为我们将证明肽片段的局部递送。凝溶胶蛋白可减少气道平滑肌收缩和过敏性肺部炎症。由成功的科学家和医师科学家组成的指导委员会将提供科学的指导研究计划各个方面的专业知识，包括离子通道生理学、钙信号传导、Th2 肺炎症、肺免疫学和巨噬细胞生物学的全面计划。课程和培训由具有精密切割肺切片专业知识的其他合作者补充磁扭转细胞细胞仪将扩大研究培训和职业发展的研究课题。是气道平滑肌病理生理学和肺免疫领域独立研究的理想途径总的来说，这个 K08 提案概述了一个强有力的途径。科学独立性以及作为一名医师科学家成功和持续职业生涯的基础。