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Etiology and treatment for the skeletal defects caused by Spermine Synthase deficiency

Award Number: R01AR085746
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Etiology and treatment for the skeletal defects caused by Spermine Synthase deficiency - Etiology and treatment for the skeletal defects caused by Spermine Synthase deficiency Polyamines are polycations ubiquitously found in almost every eukaryotic organism. They play important roles within cells, interacting with negatively charged molecules such as chromatin, phospholipids, and ion channels. In mammals, the main polyamines are ornithine, putrescine, spermidine, and spermine. Recently, polyamines uptake has been associated with extended lifespan, but also cancer progression. In bone biology, the role of polyamines remains largely understudied. Snyder-Robinson Syndrome (SRS) is a rare X-linked disorder characterized by intellectual disabilities and severe skeletal defects, including scoliosis, kyphoscoliosis and osteoporosis, where children with SRS often suffer fractures even in the absence of trauma. SRS patients harbor loss-of-function mutations in the gene coding for Spermine synthase (SMS), which catalyzes the conversion of spermidine into spermine. Therefore, SRS patients exhibit an increase in spermidine to spermine ratio, which is pathognomonic of SRS. However, how this polyamine imbalance causes SRS remains unknown. Aim 1 focuses on uncovering the exact mechanism for how SMS-deficiency leads to impaired mineralization. Previous work and preliminary results suggest a pivotal role for excess spermidine causing inadequate hypusination of eIF5A and impaired mitochondrial secretion of calcium phosphate. In Aim 2, we propose to generate conditional SMS-knock out mice (Ubc-creERT2; Smsf) to induce a global loss-of-function that mimics disrupted Sms as occurs in SRS. These mice show the expected polyamine imbalance and recapitulate the osteoporotic phenotype seen SRS. Our proposed studies will establish a causal connection in between SMS deficiency, mitochondrial function, and impaired osteogenesis. Also in Aim 2, we will elucidate if the observed skeletal defects arise from a skeletally-autonomous manner, by generation of Prrx1-creERT2; Smsf mice. For Aim 3, we will test the efficacy of osteoanabolic drugs to improve bone health in SMS-cKO mice and a compound to modulate polyamine levels.


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 = $596,378 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/7/2026	NEW	$596,378
														Subtotal = $596,378

Grand Total All Awards = $596,378

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Etiology and treatment for the skeletal defects caused by Spermine Synthase deficiency

Award Number: R01AR085746

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/07/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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