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The etiology of skeletal deficits in prepubertal Down syndrome mouse models

Award Number: F31AR087234
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 09/14/2028

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The etiology of skeletal deficits in prepubertal Down syndrome mouse models - PROJECT SUMMARY: All individuals with Down syndrome (DS) or Trisomy 21 (Ts21) present with skeletal insufficiency due to triplication of human chromosome 21 (Hsa21). Skeletal insufficiency leads to an increased risk of early-onset osteoporosis and mortality-causing fractures in people with DS. The presence and severity of skeletal insufficiency in DS is sexually dimorphic, where men with DS tend to have more deficits than women with DS depending on age, skeletal site, and bone compartment. There have been no clinical trials targeting the treatment of skeletal deficits in individuals with DS, despite the clear issue, due to a lack of information regarding the sex-specific mechanisms behind DS-associated skeletal deficits. Sexually dimorphic skeletal insufficiency in the Ts21 skeleton occurs prior to puberty in both sexes and despite seemingly normal sex hormone levels, suggesting other factors are likely contributing. There is a critical need to understand the extent of and mechanism behind sexually dimorphic DS-associated skeletal phenotypes to design treatments to improve skeletal phenotypes. The long-term goal of this research is to identify sex-specific factors other than sex hormone levels, such as sex hormone receptor signaling or sex chromosome gene interactions, to lead to targetable mechanisms to improve bone health in individuals with DS. This will be accomplished by utilizing the Dp16 DS mouse model, which have shown robust sexual dimorphism in long bone phenotypes, and the Four Core Genotypes (FCG) mouse, which uncouples sex chromosome complement from gonadal sex to understand their independent contributions, generating 8 types of offspring (Dp16-FCG). Aim 1 will quantify the structural and mechanical properties of Dp16-FCG long bones around puberty. Aim 2 will establish cellular mechanisms and growth patterns within long bones of prepubertal Dp16-FCG mice. Aim 3 will measure sex hormone signaling around puberty in biospecimens from individuals with DS and Dp16-FCG offspring. Completion of these aims will assess the impact of sex chromosome complement and gonadal sex on whole bone to cellular skeletal phenotypes in DS mice during a targetable window of development and find the mechanism for sex-specific bone development in DS. This work will also establish a tool for the DS research community to investigate mechanisms of sexual dimorphism in other phenotypes.


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: 2027 ( Subtotal = $0 )
2027	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	10/1/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $38,628 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/9/2026	NEW	$38,628
														Subtotal = $38,628

Grand Total All Awards = $38,628

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The etiology of skeletal deficits in prepubertal Down syndrome mouse models

Award Number: F31AR087234

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 09/14/2028

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