Pathogenesis-Driven Therapeutic Development for Pulmonary Alveolar Microlithiasis

肺泡微石症的发病机制驱动的治疗开发

基本信息

批准号：
9032527
负责人：
Francis Xavier McCormack
金额：
$ 39.47万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9032527
关键词：
Adoptive Transfer Affect Alveolar Alveolar Macrophages Alveolus Animals Area Arsenates Automobile Driving Calcium Calcium ion Carrier Proteins Catabolism Cells Cessation of life Chest Cicatrix Clinical Trials Collagen Complex Crystal Formation DNA Sequence Alteration Data Defect Deposition Diffuse Disease Edetic Acid Enzyme-Linked Immunosorbent Assay Epithelial Epithelium Excision Failure Family Fibroblasts Fibrosis Foamy Macrophage Functional disorder Genes Genetic Goals Health Histologic Homeostasis Human Hypoxemia Immunohistochemistry Individual Infiltration Inflammation Inflammatory Inorganic Phosphate Transporter Intervention Trial Intestines Ions Irrigation Kidney Kinetics Lecithin Life Lipids Liquid substance Lung Lung Inflammation Lung Lavage Fluid Lung diseases Mammary gland Measures Metabolism Molecular Mus Mutation Particulate Pathogenesis Patients Phagocytosis Phospholipids Physiology Prostate Protein Array Proteins Protons Pulmonary Fibrosis Pulmonary Hypertension Pulmonary Inflammation Respiratory Failure Role Serum Skin Sodium Stress Structure of parenchyma of lung Testing Testis Therapeutic Time Transgenic Organisms Western Blotting Work alveolar epithelium alveolar homeostasis alveolar type II cell base biomarker discovery calcium phosphate candidate marker chelation clinical biomarkers cytokine density effective therapy fibrogenesis gene correction genetic analysis human disease in vivo inorganic phosphate interstitial microCT middle age mouse model postnatal pre-clinical research study sodium phosphate solute surfactant symporter therapeutic development treatment strategy uptake

项目摘要

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.

描述（由申请人提供）：肺泡微石症（PAM）是一种罕见的常染色体隐性肺部疾病，与肺泡室中磷酸钙微石的积聚有关。该疾病在生命早期通常无症状，但更多情况下会进展为呼吸衰竭和死亡。 2006 年，基因分析显示，超过一半的患者出现 PAM 是由于 SLC34A2 基因失活突变所致。它编码一种在肺泡 II 型细胞上表达的关键磷酸盐转运蛋白 Npt2b。我们的工作假设是，由于 Npt2b 功能丧失而导致肺泡积聚，导致磷酸钙晶体形成、肺部炎症、表面活性剂代谢和功能受损以及肺纤维化。通过对 Npt2b 进行上皮特异性删除，创建了 PAM 小鼠模型，该模型已被证明是对人类状况的惊人真实模仿，这些动物形成了丰富的微石形成，影响了几乎所有的动物。我们在这个项目中的目标是基于对疾病发病机制的透彻理解，制定治疗 PAM 的策略。完成三个紧密结合的目标在第一个目标中，我们将研究微石形成的机制，包括石头的分子组成、微石积累的动力学以及光谱、细胞。维持磷酸盐稳态的转运蛋白的定位、定向和功能在第二个目标中，我们将研究磷酸盐代谢在肺泡稳态中的作用，包括导致磷脂沉积和纤维化的机制。在第三个目标中，我们将使用 Npt2b-/-。小鼠作为试验基于发病机制的疗法的平台，包括基因校正、钙螯合、抑制磷酸钙晶体形成，成功完成这些特定目标将为 PAM 患者进行临床试验提供所需的临床前数据。