Summary
This project investigates how cellular senescence in osteoprogenitors and osteocytes contributes to age-related bone loss, specifically examining differential mechanisms in cortical versus trabecular bone.
Different consequences of cellular aging in cortical versus cancellous bone- Resubmission
US · IL
NIH
grant
open
#nih-5R01AG068449-05
What they want
The research aims to determine if DNA damage in osteoblast lineage cells induces senescence and reduces bone mass using genetically modified mice and senolytics. It will also investigate the role of the p53/p21 pathway in osteoprogenitors and the differential contribution of senescent osteocytes (via GATA4) to bone resorption in cortical versus trabecular bone during aging.
Deliverables
- Data on whether DNA damage in osteoblast lineage cells is sufficient to induce senescence and reduce bone mass
- Identification of components of the phenotype due to senescence using senolytic PZ15227
- Data on the contribution of the p53/p21 pathway in osteoprogenitors to skeletal aging
- Data on the differential contribution of senescent osteocytes to increased bone resorption in trabecular versus cortical bone
- Quantification of osteocyte senescence in cortical versus trabecular bone
- Determination of whether senescent osteocytes express higher levels of RANKL
- Establishment of whether senescence of osteoprogenitors and osteocytes contributes to age-related bone mass loss
- Clarification of different aging mechanisms in cortical versus trabecular bone
Technical requirements
- Generation of mice with oxidative stress-induced senescence in either the entire osteoblast lineage or only in mature osteoblasts and osteocytes
- Administration of the senolytic PZ15227
- Aging mice with p53 or p21 loss-of-function
- Aging mice with GATA4 loss-of-function in osteocytes
- Quantification of osteocyte senescence
- Determination of RANKL expression levels
