Neurotrophins in the Lung

肺中的神经营养素

• 批准号: 8634922
• 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/8634922
• 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 Factor; Human; Immigration; In Vitro; Inflammation; Inflammatory; Interleukin-13; Link; Lung; Matrix Metalloproteinases; Mechanics; Mediating; Mediator of activation protein; Modeling; Mus; Neurotrophic Tyrosine Kinase Receptor Type 2; Oral; Pharmaceutical Preparations; Process; Production; Proteins; Pulmonary Emphysema; Receptor Activation; Receptor Signaling; Role; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Structure; TNF gene; Testing; Tissue Inhibitor of Metalloproteinase-1; Tissue Model; Transgenic Organisms; Work; airway remodeling; asthmatic airway; autocrine; base; clinically significant; cytokine; feeding; human data; in vivo; inhibitor/antagonist; migration; mouse model; muscle form; neurotrophic factor; novel; novel therapeutics; paracrine; public health relevance; 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（由申请人提供）：哮喘中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 通过分泌因子、调节细胞外基质 (ECM) 组成和增强增殖/迁移发挥积极作用。因此，了解炎症产生重塑的机制是新治疗策略的关键。我们之前的资助周期强调了神经营养蛋白脑源性神经营养因子 (BDNF) 的新作用，表明 BDNF 增强 ASM [Ca2+]I 和收缩力，增强炎症的影响。我们现在的研究表明，ASM不仅是BDNF的靶点，也是BDNF的来源。首次续签的重点是了解 ASM 衍生的 BDNF 在哮喘背景下炎症引起的气道结构和功能变化中的自分泌/旁分泌作用。根据初步数据，我们认为 BDNF 是重塑的关键参与者。在此，BDNF 可能与基质金属蛋白酶 (MMP) MMP-2 和 MMP-9 有关，因为它们在裂解分泌的 BDNF 中发挥作用，并且 BDNF 反过来调节 MMP 的数据有限。我们认为 BDNF 和 MMP 形成一个由炎症引发的相互相互作用的前馈回路，并且 BDNF 介导和调节炎症对 ECM 产生和 ASM 增殖/迁移的影响。与哮喘相关，初步数据显示，在哮喘人类气道和过敏性哮喘小鼠模型中，BDNF 表达及其对重塑的影响增强。因此，我们的总体假设是，ASM 衍生的 BDNF 对于哮喘炎症诱导的气道重塑至关重要，影响 ECM 组成以及 ASM 增殖和迁移。在拟议的研究中，我们将通过四个具体目标来测试这一主题： 目标 1：研究炎症增强人类气道表达和释放的机制；目标 2：研究增强炎症对人类 ASM 产生 ECM 影响的机制；目标 3：研究 ASM 衍生的 BDNF ASM 衍生的 BDNF 增强人类 ASM 增殖和迁移的炎症作用的机制；目标 4：在混合过敏原小鼠模型中检查改变的 BDNF 信号传导对气道重塑的体内影响。目标 1-3 将利用来自轻度或中度哮喘患者与非哮喘患者的去皮 ASM 组织和细胞来检查细胞因子（TNF¿ 与 IL-13）对 BDNF 的增强（目标 1），重叠与不同的信号传导机制，通过该机制介导和调节细胞因子对 MMP-2 和 MMP-9（ECM 蛋白）的影响 纤连蛋白和胶原蛋白（目标 2），以及在 ECM 成分改变的情况下增强 ASM 增殖和迁移（目标 3）。体外数据将在混合过敏原小鼠哮喘模型中的 Aim 4 体内进行整合，其中 BDNF 受体激活将在转基因 TrkB 敲入小鼠中受到抑制。我们研究的临床意义在于，可以针对重塑具有多效性作用的“上游”机制来限制哮喘的这种不可逆转的特征。 ASM衍生的BDNF