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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.

项目总结/文摘