Role of Notch signaling in fracture healing as a function of aging

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Fragility fractures in the elderly represent a substantial source of morbidity and mortality to our aging population and are a great cost to society as a whole. The ability to heal fractures decreases with age where at one extreme, a skeletally immature child can heal a fracture in several weeks and at the other, an octogenarian may take several months or more to heal the same fracture. At the cellular and molecular level, there are several lines of evidence suggesting that Notch signaling is an important determinant in bone formation and fracture healing. Additionally, studies have shown that decreased Notch signaling with aging is responsible for reduced muscle regeneration with aging. We hypothesize that the decrease in fracture healing with aging is associated with alterations in Notch signaling. To test this hypothesis we propose two specific aims. For the first aim we will characterize and compare Notch expression and signaling in fracture healing using young and chronologically aged mice. For the second aim we will characterize and compare the histologic and biomechanical progression of fracture healing in aged mice with Notch signaling increased. We will increase Notch signaling in a mouse model that has the Notch intracellular domain (NICD - the active signaling component) driven by the activity of Cre-recombinase. This work will provide the foundation for further investigation of the Notch pathway as a modifiable event in the acceleration of fracture healing in the elderly. PUBLIC HEALTH RELEVANCE: Fragility fractures represent a significant cause of morbidity in the elderly. These fractures take much longer to heal and with greater morbidity than fractures in the young. The work proposed in this study using a mouse model will investigate whether increasing Notch signaling can be used to promote healing of fractures in geriatric patients.