Noradrenergic mechanisms of IPF

IPF 的去甲肾上腺素能机制

• 批准号: 10584613
• 负责人: Erica L Herzog
• 金额: $ 70.71万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-05 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584613
• 关键词: Adrenergic Agents; Adult; Animal Model; Biology; Caring; Catabolism; Cells; Cicatrix; Clinical; Complication; Cues; DCC gene; Dependence; Disease; Enzymes; Epithelial Cells; Extracellular Matrix; Family; Fibroblasts; Fibrosis; Genetic; Grant; Human; Immunology; Injury; Intervention; Knock-out; Knockout Mice; Link; Literature; Lung; Lung Transplantation; Macrophage; Mediating; Methaqualone; Modeling; Monoamine Oxidase A; Mus; Nerve; Nerve Tissue; Neurosciences; Norepinephrine; Organ; Outcome; Pathogenesis; Pathogenicity; Pathology; Patients; Pattern; Peripheral; Process; Progressive Disease; Proliferating; Pulmonary Fibrosis; Recycling; Reporter; Rodent; Sampling; Scientist; Slice; Structure of parenchyma of lung; Testing; Therapeutic; Tissue Sample; Tissues; Translating; Transplantation; Vision; antagonist; cost; effective therapy; experience; fibrotic lung; gain of function; human disease; idiopathic pulmonary fibrosis; improved; insight; knock-down; loss of function; lung repair; member; microCT; mimetics; mouse model; nerve supply; noradrenaline transporter; noradrenergic; overexpression; pharmacologic; receptor; side effect; single cell sequencing; solute

ABSTRACT The pulmonary fibrosis that accompanies many conditions is characterized by progressive scar formation in the adult human lung. Regardless of the underlying disease state, the presence of this complication portends a worse outcome that is curable only by lung transplantation. Proposed pathogenic mechanisms suggest a poorly understood interaction between epithelial cells and fibroblasts that is orchestrated by microenvironmental cues. Understanding these aspects in the fibrotic microenvironment is of particular importance in diseases such as Idiopathic Pulmonary Fibrosis (IPF) where patients present with established and often progressive disease. As a result, identification of intervenable processes that can be targeted for safe and effective therapies remains a critical unmet need. It is therefore relevant that in a groundbreaking set of studies we have found that fibrotic lungs are enriched for ectopically patterned adrenergic nerves, that these nerves drive fibrosis by releasing NA, that NA driven fibrosis can be treated with α1 adrenoreceptor antagonists. This axis is active in IPF where lung tissues are enriched for markers of adrenergic innervation and NA, and patients treated with α1 adrenoreceptor antagonists experience improved clinical outcomes. We will now determine how NA accumulates in fibrotic lungs and define its fibrogenic functions. For example, while we have found that adrenergic nerve remodeling is stimulated by the dependence receptor deleted in colorectal carcinoma (DCC), the mechanism(s) of this observation are unknown. We have found that fibrotic lung macrophages are deficient in NA catabolism machinery, but whether they contribute to fibrosis via perturbed NA recycling has not been shown. Finally, we have found an association between fibroblast proliferation and α1 adrenoreceptor subtype ADRA1D in fibrotic mouse models and in human IPF that requires more study. This application will explore the mechanistic impact and therapeutic potential of these findings using a unified vision and conceptual framework that will study how nerve-derived NA accumulates in the lung and causes fibrosis. We propose an integrated project that pursues three independent aims using a translational platform combining two animal models, manipulation of adrenergic nerves, neuroengineering, cell specific knockout mice, genetic and pharmacologic gain and loss of function approaches, ex vivo study of human cells and tissues, single cell sequencing, and microCT. The first aim will probe whether adrenergic nerve remodeling and accumulation of fibrostimulatory NA requires expression of the dependence receptor deleted in colorectal carcinoma (DCC) on adrenergic nerves in the lung. The second aim will determine if perturbed NA recycling by macrophages exacerbates fibrosis in animal models and in human cells and tissues. The third aim will use cell specific knockout mice and primary human cells and tissues to determine wither NA-associated lung fibrosis requires ADRA1D-expressing fibroblasts. If successful, our project will produce paradigm shifting results that will change the way we view – and treat – fibrosis in the adult lung.

抽象的 涉及许多疾病的肺纤维化的特征是在 成人人类肺。不管潜在疾病状态如何，这种并发症的存在预示 更糟糕的结果仅通过肺移植才能治愈。提出的致病机制表明很差 了解由微环境提示策划的上皮细胞和成纤维细胞之间的相互作用。 在纤维化微环境中了解这些方面在诸如疾病中尤其重要 特发性肺纤维化（IPF），患者患有已建立且经常进行性疾病。作为 结果，可以识别可以针对安全有效疗法的可间外过程 关键的未满足需求。因此，相关的是，在一组开创性的研究中，我们发现纤维化 肺部富含异位图案的肾上腺神经，这些神经通过释放Na，促进纤维化， NA驱动的纤维化可以用α1肾上腺受体拮抗剂处理。该轴活动在IPF中活跃 组织富含肾上腺神经和NA的标记，并用α1肾上腺受体治疗的患者 拮抗剂经历了改善的临床结果。现在我们将确定NA如何在纤维化中积累 肺并定义其纤维化功能。例如，尽管我们发现肾上腺神经重塑 在结直肠癌（DCC）中删除的依赖受体刺激。 观察是未知的。我们发现纤维化的肺巨噬细胞缺乏NA分解代谢 机械，但是尚未显示它们是否通过扰动的NA回收有助于纤维化。最后，我们 在纤维化中发现了成纤维细胞增殖与α1肾上腺素亚型ADRA1D之间的关联 小鼠模型和人类IPF需要更多的研究。该应用程序将探索机械影响 这些发现的治疗潜力使用统一的愿景和概念框架，这些框架将研究如何 神经衍生的NA在肺中积聚并引起纤维化。我们提出了一个综合项目 使用两个动物模型的翻译平台的三个独立目标，操纵肾上腺素 神经，神经工程，细胞特异性基因敲除小鼠，遗传和药物增益和功能丧失 方法，人体细胞和组织的离体研究，单细胞测序和Microct。第一个目标 探测肾上腺神经重塑和纤维刺激性NA的积累是否需要表达 在结直肠癌（DCC）中删除的依赖受体对肺部肾上腺神经。第二个目标 将确定巨噬细胞在动物模型和人类中的纤维化是否加剧了纤维化的纤维化。 细胞和组织。第三个目标将使用细胞特异性基因敲除小鼠，原代人细胞和组织 用NA相关的肺纤维化确定需要表达ADRA1D的成纤维细胞。如果成功，我们的项目 将产生范式转移结果，以改变我们在成年肺中观察和治疗纤维化的方式。