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：
9247827
负责人：
Francis Xavier McCormack
金额：
$ 39.45万
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/9247827
关键词：
Adoptive Transfer Affect Alveolar Alveolar Macrophages Alveolus Animals Area Arsenates Automobile Driving Calcified Calcium Calcium ion Carrier Proteins Catabolism Cells Cessation of life Chest Cicatrix Clinical Trials Collagen Complex Crystal Formation Crystallization DNA Sequence Alteration Data Defect Deposition Diagnostic radiologic examination Diffuse Disease Edetic Acid Enzyme-Linked Immunosorbent Assay Epithelial Epithelium Excision Failure Family Fibroblasts Fibrosis Foamy Macrophage Functional disorder Genes Genetic Goals Histologic Homeostasis Human Hypoxemia Immunohistochemistry Impairment 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 Pharmacological Treatment Pharmacology 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 alveolar epithelium alveolar homeostasis alveolar type II cell base biomarker discovery calcification calcium phosphate candidate marker chelation clinical biomarkers cytokine delta protein density effective therapy experimental study fibrogenesis gene correction genetic analysis human disease in vivo inorganic phosphate interstitial microCT middle age mouse model postnatal pre-clinical protein profiling public health relevance 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（由适用提供）：肺肺泡微石质（PAM）很少见，常染色体隐性肺疾病与肺泡室中磷酸钙微石的积累相关。这种疾病在早期通常是不对称的，但是在中年有超过一半的患者中，该疾病已发展为呼吸衰竭和死亡。在2006年，通过遗传分析揭示了PAM是由于Slc34a2中的突变灭活，该突变是一种编码在称为NPT2B的肺泡II型细胞上表达的磷酸盐键转运蛋白的基因。我们的工作假设是，由于NPT2B功能的丧失，肺泡的积累会导致磷酸钙晶体形成，肺部感染，生存代谢和功能受损以及肺纤维化。我们已经通过NPT2B的上皮特异性缺失创建了PAM的小鼠模型，该模型被证明是人类条件的非常真实的模仿。这些动物形成了丰富的微石形成，几乎影响了几乎所有肺泡，弥漫性射线照相占领，限制性肺部生理学，意外的肺泡磷脂病，泡沫巨噬细胞浸润和注射以及适度的肺纤维化。我们在该项目中的目标是基于对疾病发病机理的透彻理解，通过完成三个紧密整合的目的来制定治疗PAM的策略。在第一个目的中，我们将研究微石形成的机制，包括石材的分子组成，微石的积累动力学以及谱，细胞定位，转运蛋白的谱系稳态稳态。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，包括负责磷脂病和纤维化的机制。在第三个目标中，我们将使用NPT2B - / - 小鼠作为基于试验的疗法的平台，包括遗传校正，螯合钙，抑制磷酸钙晶体形成，并通过其他转运蛋白刺激替代性肺泡磷酸盐出口。这些特定目标的成功完成将为PAM患者进行临床试验所需的临床前数据。