Neurotrophins in the Lung

肺中的神经营养素

基本信息

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
项目类别：
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

项目摘要

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）：哮喘中的气道重塑增加了纤维化、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/迁移来积极贡献。，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 和收缩性，增强炎症的影响，我们现在的研究表明，ASM 不仅是 BDNF 的靶点，而且是 BDNF 的来源。这项资助的首次更新的重点是了解自分泌/。 ASM 衍生的 BDNF 在哮喘引起的气道结构和功能变化中的旁分泌作用根据初步数据，我们认为 BDNF 可能在重塑中发挥关键作用。考虑到它们在裂解分泌的 BDNF 中的作用，以及 BDNF 反向调节 MMP 的有限数据，我们认为 BDNF 和 MMP 形成了一个相互相互作用的前馈循环，因此可能与基质金属蛋白酶 (MMP) MMP-2 和 MMP-9 有关。初步数据表明，BDNF 介导和调节炎症对 ECM 产生和 ASM 增殖/迁移的影响。 BDNF 表达及其对重塑的影响在哮喘人类气道和过敏性哮喘小鼠模型中增强，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 组成和 ASM 增殖。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：研究增强炎症的机制；炎症对人类 ASM 产生 ECM 的影响；目标 3：研究 ASM 衍生的 BDNF ASM 衍生的 BDNF 增强炎症对人类 ASM 增殖和迁移的影响的机制；目标 4：研究改变的体内效应；混合过敏原小鼠模型中气道重塑的 BDNF 信号传导将利用来自轻度或中度哮喘患者的人类上皮剥脱的 ASM 组织和细胞。非哮喘患者检查细胞因子（TNF¿与 IL-13）增强 BDNF（目标 1），通过重叠与不同的信号机制介导和调节细胞因子对 MMP-2 和 MMP-9、ECM 蛋白纤连蛋白和胶原蛋白的影响（目标 2），以及增强在改变 ECM 成分的情况下，ASM 增殖和迁移（目标 3）将在混合过敏原小鼠哮喘模型中的体内整合，其中 BDNF 受体激活。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 ASM 衍生的 BDNF 的这种不可逆转的特征。