Neurotrophins in the Lung

肺中的神经营养素

• 批准号: 9002085
• 负责人: Y. S. Prakash
• 金额: $ 40.94万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9002085
• 关键词: Affect; Affinity; Allergens; Animal Model; Area; Asthma; Biology; Brain-Derived Neurotrophic Factor; Cell Count; Cell Proliferation; Cells; Cleaved cell; Collagen; Complex; Data; Deposition; Development; Disease; Epithelial; Epithelium; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Space; Extrinsic asthma; Family; Fibronectins; Fibrosis; Functional disorder; Gelatinase A; Gelatinase B; Grant; Growth; Health; Human; Immigration; In Vitro; Inflammation; Inflammatory; Interleukin-13; Knock-in Mouse; Link; Lung; Matrix Metalloproteinases; Mechanics; Mediating; Mediator of activation protein; Modeling; Muscle; Neurotrophic Tyrosine Kinase Receptor Type 2; Oral; Pharmaceutical Preparations; Process; Production; Proteins; Pulmonary Emphysema; Receptor Activation; Receptor Signaling; Role; Signal Transduction; Smooth Muscle Myocytes; Source; Structure; TNF gene; Testing; Tissue Inhibitor of Metalloproteinase-1; Tissue Model; Transgenic Organisms; Work; airway remodeling; asthmatic; asthmatic airway; autocrine; base; clinically significant; cytokine; feeding; human data; in vivo; inhibitor/antagonist; migration; mouse allergen; mouse model; muscle form; neurotrophic factor; novel; novel therapeutics; paracrine; pleiotropism; respiratory smooth muscle; small molecule

DESCRIPTION (provided by applicant): Airway remodeling in asthma involves increased fibrosis, airway smooth muscle (ASM) proliferation and migration. Inflammation drives remodeling, but ASM actively contributes by secreting factors, regulating extracellular matrix (ECM) composition and enhancing proliferation/migration. Accordingly, understanding mechanisms by which inflammation produces remodeling is key to novel therapeutic strategies. Our previous grant cycle highlighted the novel role of the neurotrophin brain-derived neurotrophic factor (BDNF), showing that BDNF enhances ASM [Ca2+]I and contractility, potentiating the effects of inflammation. Our studies now show that ASM is not only a target, but also a source of BDNF. The focus of the first renewal of this grant is to understand the autocrine/paracrine role of ASM-derived BDNF in inflammation-induced changes to airway structure and function in the context of asthma. Based on preliminary data, we believe that BDNF is a key player in remodeling. Here, BDNF may be linked to the matrix metalloproteinases (MMPs) MMP-2 and MMP-9, given their role in cleaving secreted BDNF, and limited data that BDNF conversely regulates MMPs. We propose that BDNF and MMPs form a mutually interactive, feed-forward loop stoked by inflammation, and that BDNF mediates and modulates inflammation effects on ECM production and ASM proliferation/migration. Relevant to asthma, preliminary data show that BDNF expression and effects on remodeling are enhanced in asthmatic human airway, and in a mouse model of allergic asthma. Accordingly, our overall hypothesis is that ASM-derived BDNF is central to inflammation-induced airway remodeling in asthma, affecting ECM composition and ASM proliferation and migration. In the proposed studies, we will test this theme via four Specific Aims: Aim 1: To examine mechanisms by which inflammation enhances expression and release in human airways; Aim 2: To examine the mechanisms by which potentiates inflammation effects on ECM production by human ASM; Aim 3: To examine ASM-derived BDNF ASM-derived BDNF the mechanisms by which ASM-derived BDNF potentiates inflammation effects on human ASM proliferation and migration; Aim 4: To examine in vivo effects of altered BDNF signaling on airway remodeling in a mixed allergen mouse model. Aims 1-3 will utilize human epithelium-denuded ASM tissues and cells from mild or moderate asthmatics vs. non-asthmatics to examine cytokine (TNF¿ vs. IL-13) enhancement of BDNF (Aim 1), overlapping vs. distinct signaling mechanisms by which mediates and modulates cytokine effects on MMP-2 and MMP-9, the ECM proteins fibronectin and collagen (Aim 2), and enhancement of ASM proliferation and migration in the setting of altered ECM composition (Aim 3). In vitro data will be integrated in vivo in Aim 4 in a mixed allergen mouse asthma model where BDNF receptor activation will be inhibited in a transgenic TrkB knockin mouse. The clinical significance of our studies lies in the potential that an "upstream" mechanism with pleiotropic effects on remodeling can be targeted to limit this irreversible feature of asthma. ASM-derived BDNF

描述（由应用提供）：哮喘的气道重塑涉及纤维化增加，气道平滑肌（ASM）增殖和迁移。炎症驱动重塑，但ASM通过分泌因素，调节细胞外基质（ECM）组成并增强增殖/迁移而积极贡献。根据了解炎症产生重塑的机制是新型治疗策略的关键。我们以前的赠款周期强调了神经营养蛋白脑衍生的神经营养因子（BDNF）的新作用，表明BDNF增强了ASM [Ca2+] I和收缩力，并使感染的影响潜在。现在，我们的研究表明，ASM不仅是目标，而且是BDNF的来源。该赠款的第一个续约的重点是了解ASM衍生的BDNF在注射诱导的气道结构变化中的自分泌/旁分泌作用，并在哮喘的背景下。基于初步数据，我们认为BDNF是重塑的关键参与者。在这里，BDNF可以与基质金属蛋白酶（MMPS）MMP-2和MMP-9相关，鉴于它们在分裂分泌的BDNF中的作用，并且BDNF相反调节MMP的有限数据。我们建议BDNF和MMP形成一种相互互动的，馈入的环路，并通过注射刺激，并且BDNF介导并调节炎症对ECM产生和ASM增殖/迁移的影响。与哮喘相关的初步数据表明，在哮喘的人类气道以及过敏性哮喘的小鼠模型中，BDNF的表达和对重塑的影响得到了增强。根据拟议的研究，我们将通过四个特定目的测试该主题：目标1：检查炎症可以增强人类气道中表达和释放的机制；目的2：检查人类ASM对ECM生产的影响的机制；目标3：检查ASM衍生的BDNF ASM衍生的BDNF的机制，通过ASM衍生的BDNF增强注射对人ASM增殖和迁移的影响；目标4：检查混合过敏原小鼠模型中BDNF信号改变对气道重塑的体内影响。目的1-3将利用人类上皮的ASM组织和细胞从轻度或中度或中等的哮喘患者与非偶然学对bdnf（AIM 1）增强（AIM 1）的增强（AIM 1），重叠与9个不同的信号机制的ECMMP-2-2-2-2-2-2-蛋白质纤连蛋白和胶原蛋白（AIM 2），以及在改变ECM组成的情况下ASM增殖和迁移的增强（AIM 3）。在混合过敏原小鼠哮喘模型中，将在AIM 4中将体外数据集成在体内，其中BDNF受体激活将在转基因TRKB敲击小鼠中抑制。我们研究的临床意义在于潜在的潜力是，可以针对重塑的“上游”机制，以限制哮喘的这种不可逆的特征。 ASM衍生的BDNF