Osteoclast Dysfunction in Lysinuric Protein Intolerance (LPI) - PROJECT SUMMARY/ABSTRACT Lysinuric protein intolerance (LPI) is an inborn error of metabolism associated with multiple life-threatening complications in children. LPI results from biallelic loss of function variants in SLC7A7, which encodes a subunit of the y+L transporter (y+LAT-1). Dysfunction of this transporter impairs absorption of arginine, ornithine, and lysine by renal and intestinal epithelial cells as these amino acids may be intracellularly trapped. Low circulating levels of arginine and ornithine result in urea cycle (UC) dysfunction and the risk of hyperammonemia. These complications are managed with protein restriction and citrulline supplementation. However, children with LPI also develop other potentially fatal complications that do not respond to protein restriction and citrulline supplementation such as pulmonary alveolar proteinosis, hemophagocytic lymphohistiocytosis, early-onset autoimmunity, and juvenile osteoporosis. The underlying mechanisms of these complications in LPI are unknown, and there are no therapies specifically targeting these non-UC phenotypes. Myeloid cells have high levels of Slc7a7 expression, suggesting that dysfunction of myeloid cells may cause the non-UC phenotypes. Our lab has created a tissue specific conditional knockout mouse model that recapitulates LPI complications seen in children including osteopenia. I propose to use this mouse model to understand the metabolic and cellular mechanisms that underlie reduced bone mass in LPI. My central hypothesis is that juvenile osteoporosis in LPI is the result of arginine retention in cells of the hematopoietic lineage, which promotes inflammation and drives osteoclastogenesis. I will address this hypothesis with two aims. Aim 1 will demonstrate osteoporosis in our mouse model and determine if bisphosphonates are a suitable therapy for treating juvenile osteoporosis in LPI. Aim 2 will identify the metabolic mechanisms that explain how osteoclast progenitors contribute to the reduced bone mass phenotype in LPI. Together, these aims will demonstrate osteoclast dysfunction as the mechanism underlying juvenile osteoporosis in LPI. The long-term goal of these studies is to identify targeted therapies of osteoporosis that benefit children with LPI in addition to broadening our understanding of osteoimmunity and metabolism. With the clinical and scientific training environments offered at the Baylor College of Medicine and Texas Medical Center, the applicant is primed to accomplish these aims while working towards a future career as a pediatric physician-scientist.
