Pathogenesis-Driven Therapeutic Development for Pulmonary Alveolar Microlithiasis

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 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.