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Osteoclast Dysfunction in Lysinuric Protein Intolerance (LPI)

Award Number: F30HD121206
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/16/2026
PERIOD OF PERFORMANCE END DATE: 07/15/2029

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,526 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	1	2/13/2026	NEW	$49,950
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	001	1	2/13/2026	NEW	$0
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	002	1	4/2/2026	NEW	$576
														Subtotal = $50,526

Grand Total All Awards = $50,526

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Osteoclast Dysfunction in Lysinuric Protein Intolerance (LPI)

Award Number: F30HD121206

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/16/2026

PERIOD OF PERFORMANCE END DATE: 07/15/2029

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