Promoting Skeletal Regeneration in Aged Mice Summary In this study we will investigate the mechanisms behind failed bone and soft tissue regeneration in the aged digit amputation mouse model. While the digit regeneration model has gained considerable traction in recent years and resulted in a substantial amount of knowledge regarding mechanisms underlying regeneration, this is the first study that will use this model to explore regeneration the context of aging. We show that regeneration fails in this model in ways that are similar to compromised bone turnover in old age, including exacerbated bone degradation activity and the attenuated ability to mount a successful regenerative bone response. This age-related response is similar to the one seen when we applying increased oxygen tension, disrupting the native oxygen microenvironment in the regenerating digit, which requires an oscillation between both hypoxic and normoxic oxygen environments for successful regeneration. While it is clear that the oxygen microenvironment of the digit is dynamic and critical to successful regeneration, it is not known how oxygen cues the regenerative process and whether or not this is directly linked to changes in cell metabolism or metabolic switching, as is seen in certain cancers. The studies outlined in this project will explore the mechanisms through which regeneration fails during aging by specifically investigating the role of oxygen signals and cellular metabolism. We will test the hypothesis that regeneration fails in aging as a direct result of the inability of key cell populations to successfully execute metabolic switching between mitochondrial respiration and glycolytic activity and to respond to changes in the oxygen microenvironment. To test this hypothesis we will evaluate regeneration in both aged outbred mice (Aim 1) and in a transgenic mouse model of aging with metabolic syndrome (Aim 2), and test the ability of these two strains of mice to respond effectively to changes in oxygen levels (Aim 3). This project will provide valuable data in both the regeneration and aging fields and will yield new mechanistic insights that will help guide future therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103629-09
Application #
9932384
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Tulane University
Department
Type
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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Zhang, Qian; Chen, Yujue; Yang, Lu et al. (2018) Multitasking Ska in Chromosome Segregation: Its Distinct Pools Might Specify Various Functions. Bioessays 40:
Kim, Sangkyu; Jazwinski, S Michal (2018) The Gut Microbiota and Healthy Aging: A Mini-Review. Gerontology 64:513-520
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Akintunde, Akinjide R; Miller, Kristin S (2018) Evaluation of microstructurally motivated constitutive models to describe age-dependent tendon healing. Biomech Model Mechanobiol 17:793-814
Kim, Sangkyu; Wyckoff, Jennifer; Morris, Anne-T et al. (2018) DNA methylation associated with healthy aging of elderly twins. Geroscience 40:469-484
Palozola, Katherine C; Donahue, Greg; Liu, Hong et al. (2017) Mitotic transcription and waves of gene reactivation during mitotic exit. Science 358:119-122
Liao, Wenjuan; Liu, Hongbing; Zhang, Yiwei et al. (2017) Ccdc3: A New P63 Target Involved in Regulation Of Liver Lipid Metabolism. Sci Rep 7:9020
Jazwinski, S Michal; Kim, Sangkyu (2017) Metabolic and Genetic Markers of Biological Age. Front Genet 8:64

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