Noradrenergic mechanisms of IPF

摘要 伴随许多病症的肺纤维化的特征在于肺组织中的进行性瘢痕形成。 成人肺无论潜在的疾病状态如何，这种并发症的存在预示着 只有通过肺移植才能治愈的更糟糕的结果。提出的致病机制表明， 了解上皮细胞和成纤维细胞之间的相互作用，这是由微环境线索编排。 了解纤维化微环境中的这些方面在疾病中特别重要， 特发性肺纤维化（IPF），患者表现为已确诊且通常为进行性疾病。作为 因此，识别可干预的过程，可以针对安全和有效的治疗仍然是一个问题。 关键的未满足的需求。因此，在一组开创性的研究中，我们发现纤维化 肺富含异位图案化的肾上腺素能神经，这些神经通过释放NA驱动纤维化， NA驱动的纤维化可用α1肾上腺素受体拮抗剂治疗。该轴在IPF中活跃， 组织富含肾上腺素能神经支配和NA的标志物， 拮抗剂的临床结果得到改善。我们现在将确定NA如何在纤维化组织中积累， 肺和定义其纤维化功能。例如，虽然我们已经发现肾上腺素能神经重塑 大肠癌中缺失的依赖性受体（DCC）刺激了这种作用，其机制是 观察是未知的。我们发现纤维化肺巨噬细胞缺乏NA catalysts， 但是它们是否通过扰乱NA再循环而导致纤维化尚未显示。最后我们 已经发现纤维化中成纤维细胞增殖和α1肾上腺素受体亚型ADRA 1D之间存在关联， 在小鼠模型和人类IPF中，需要更多的研究。本应用程序将探讨机械影响 和治疗潜力，这些发现使用一个统一的视野和概念框架，将研究如何 神经源性NA在肺中积累并引起纤维化。我们提出了一个综合项目， 三个独立的目标，使用结合两种动物模型的平移平台，操纵肾上腺素能 神经，神经工程，细胞特异性敲除小鼠，遗传和药理学获得和功能丧失 方法、人体细胞和组织的离体研究、单细胞测序和microCT。第一个目标将 探讨肾上腺素能神经重塑和纤维刺激NA的积累是否需要表达 依赖性受体缺失的大肠癌（DCC）对肾上腺素能神经在肺。第二个目的 将确定巨噬细胞干扰的NA再循环是否会加重动物模型和人类的纤维化 细胞和组织。第三个目标将使用细胞特异性敲除小鼠和原代人类细胞和组织， 确定萎缩NA相关的肺纤维化需要表达ADRA1D的成纤维细胞。如果成功，我们的项目 将产生范式转变的结果，这将改变我们看待和治疗成人肺纤维化的方式。

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.