Wednesday, January 15, 2025
1/15/2025
The goal of this R21 application is to convert existing mouse models of moderate and severe Osteogenesis Imperfecta (OI) caused by type 1 collagen mutations to conditional mouse models of moderate and severe OI. Conditional mouse models offer several advantages over the existing strains. First, conditional mouse strains can be maintained and distributed by public repositories; existing strains are in individual labs, and not in repositories, because of their skeletal fragility. Second, OI is a multi-system disease that affects bone, heart, lung, tendon, ligament, and skin. When studying OI, the phenotype in one organ system (e.g., heart or lung) is confounded by disease-associated problems in another organ system (e.g., spine and ribs). Conditional mouse models in which Cre-recombinase is used to express the mutant protein in a tissue-specific manner minimizes this confounding. Currently, there are no conditional mouse models with type 1 collagen mutations, even though ~ 85% of human OI is caused by such mutations. Third, by converting existing strains to conditional strains, any new data obtained with the conditional strains can be compared to previously published data because the same mutation was studied. We will modify existing alleles by inserting a gene-trap using i- GONAD gene-editing technology. Applying gene-traps and i-GONAD will enable us to efficiently convert 4 existing OI-causing alleles (Aga2, Jrt, Brtl, and p.G610C) in mice to conditional OI-causing alleles. Mouse strains with the new conditional alleles can be distributed by public repositories. We will also determine the effect of inducing endogenous expression of mutant type 1 collagen in hypertrophic chondrocytes, since hypertrophic chondrocytes have been shown to transdifferentiate into osteoblasts and osteoprogenitors. Therefore, it is important to know if bone properties are strongly influenced by cells expressing mutant type 1 collagen that have descended from hypertrophic chondrocytes, or if unaffected bone forming cells descended from other progenitor sources compensate for, or outcompete, the mutant hypertrophic chondrocyte-derived descendants. This latter knowledge will aid investigators who are interested in using cell therapies to displace/replace mutant osteoblasts and osteoprogenitors with wild-type ones.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).