Pathogenesis-Driven Therapeutic Development for Pulmonary Alveolar Microlithiasis

 描述（由申请方提供）：肺泡微石症（PAM）是一种罕见的常染色体隐性遗传性肺部疾病，与肺泡室中磷酸钙微石蓄积相关。这种疾病通常在生命早期没有症状，但到中年时，超过一半的患者会发展为呼吸衰竭和死亡。2006年，PAM被遗传分析揭示是由于SLC 34 A2的失活突变，SLC 34 A2是一种编码在肺泡II型细胞上表达的关键磷酸盐转运蛋白Npt 2b的基因。我们的工作假设是，由于Npt 2b功能丧失导致的肺泡积聚导致磷酸钙晶体形成、肺部炎症、表面活性物质代谢和功能受损以及肺纤维化。我们已经通过上皮特异性缺失Npt 2b创建了PAM的小鼠模型，其已被证明是人类状况的非常真实的模拟物。这些动物出现大量影响几乎每个肺泡的微石形成、弥漫性影像学混浊、限制性肺生理学、意外的肺泡磷脂沉积症、泡沫状巨噬细胞浸润和炎症以及中度肺纤维化。我们在这个项目中的目标是通过完成三个紧密结合的目标，在彻底了解疾病发病机制的基础上，制定治疗PAM的策略。在第一个目标中，我们将研究微石形成的机制，包括结石的分子组成，微石积累的动力学，以及维持磷酸盐稳态的转运蛋白的光谱，细胞定位，方向和功能。在第二个目标中，我们将研究磷酸盐代谢在肺泡内环境稳定中的作用，包括磷脂沉积症和纤维化的机制。在第三个目标中，我们将使用Npt 2b-/-小鼠作为平台来试验基于发病机制的疗法，包括遗传校正、钙螯合、抑制磷酸钙晶体形成、 和刺激通过其他转运蛋白的替代性肺泡磷酸盐输出。成功完成这些特定目标将提供在PAM患者中进行临床试验所需的临床前数据。

 DESCRIPTION (provided by applicant): Pulmonary alveolar microlithiasis (PAM) is rare, autosomal recessive lung disorder associated with accumulation of calcium phosphate microliths in the alveolar compartment. The disease is often asymptomatic in early life, but progresses to respiratory failure and death in more than half of patients by middle age. In 2006, PAM was revealed by genetic analyses to be due to inactivating mutations in SLC34A2, a gene which encodes a key phosphate transporter expressed on alveolar type II cells called Npt2b. Our working hypothesis is that accumulation of alveolar due to loss of Npt2b function leads to calcium phosphate crystal formation, pulmonary inflammation, impaired surfactant metabolism and function, and pulmonary fibrosis. We have created a mouse model of PAM, by epithelium specific deletion of Npt2b, which has proven to be a remarkably authentic mimic of the human condition. The animals develop abundant microlith formation affecting nearly every alveolus, diffuse radiographic opacification, restrictive pulmonary physiology, an unexpected alveolar phospholipidosis, foamy macrophage infiltration and inflammation, and modest pulmonary fibrosis. Our goal in this project is to develop strategies for treatment of PAM, based on a thorough understanding of disease pathogenesis, through the completion of three tightly integrated aims. In the first aim we will examine the mechanisms of microlith formation, including the molecular composition of the stone, kinetics of microlith accumulation, and the spectrum, cellular localization, orientation and function of transporters that maintain phosphate homeostasis. In the second aim, we will examine the role of phosphate metabolism in alveolar homeostasis, including mechanisms responsible for phospholipidosis and fibrosis. In the third aim, we will use the Npt2b-/- mouse as a platform to trial pathogenesis-based therapies, including genetic correction, calcium chelation, inhibition of calcium phosphate crystal formation, and stimulation of alternative alveolar phosphate export via other transporters. Successful completion of these specific aims will provide the preclinical data needed to conduct a clinical trial in individuals with PAM.