Project Grant R01AR085746

This $596,378 Project Grant, awarded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846), supports research into the etiology and treatment of skeletal defects caused by spermine synthase deficiency. The award, effective July 7, 2026, through June 30, 2031, is being executed by the University of California, Davis at its Sacramento campus. The research aims to elucidate the molecular mechanisms by which spermine synthase (SMS) deficiency leads to impaired bone mineralization and skeletal pathology in Snyder-Robinson Syndrome (SRS), a rare X-linked disorder characterized by intellectual disability, severe scoliosis, kyphoscoliosis, and osteoporosis.

The funded investigation will deliver research findings through two primary research aims: (1) mechanistic studies to establish how SMS deficiency and the resulting polyamine imbalance—specifically elevated spermidine-to-spermine ratios—impairs hypusination of eukaryotic initiation factor 5A (EIF5A) and disrupts mitochondrial calcium-phosphate secretion necessary for bone mineralization; and (2) generation and characterization of conditional SMS-knockout mouse models (UBC-CREERT2; SMSF) that recapitulate the human SRS osteoporotic phenotype, establishing causal connections between SMS deficiency, mitochondrial dysfunction, and impaired osteogenesis. These research deliverables will contribute foundational knowledge toward developing targeted therapeutics for skeletal manifestations of SMS deficiency disorders.