The overall goal of Project 3 is to understand how p66Shc knockout (KO) and diet controls the regenerative and differentiation potentials of stem cells, and the consequences of this regulation in determination of resistance to cell stress and adiposity. This project has two specific aims:
Aim 1 is to further characterize the effects of the p66Shc genotype on regenerative and differentiation potentials on stem cells of multiple compartments, e.g., epithelial, hematopoietic, mesenchymal, adipose, and muscle, already defined in substantial preliminary data of the Pelicci and Rizzuto groups. The goal is to clarify the signals and the molecular checkpoints pf the proliferative and differentiation routes, and the alterations induced by patho-physiological alterations, such as obesity and hyperglycemia, as well as to determine the cellular identity of the precursor cells responsible for regeneration, and the signals and transduction mechanisms of trans-differentiation into other cell lineages. Finally, Project 3 will determine how diet, i.e., lifespan-lengthening calone restriction, low-carbohydrate diet and high-fat diet, influence stem cell proliferation and differentiation.
Aim 2 will determine the mechanism of ShcKO muscle stress resistance, investigating increased regenerative/differentiation potential of stem cells and activation of autophagy pathway. The Rizzuto group has already identified enhanced stress-induced autophagy in p66Shc -/- muscles. The project's research program will determine the basis of increased stress resistance of p66Shc muscle, which could include increased regenerative capacity, decreased differentiation to adipose, and increased autophagy. To achieve this, project personnel will investigate the signaling pathways, with major emphasis on the Akt/FoxO/Bnip pathway and on signals converging on mitochondna (assembly of regulatory complexes on the mitochondnal membrane, organelle morphology, calcium transients). Then the project will investigate these effects in the context of calorie-restriction and low-carbohydrate diets.

Public Health Relevance

The dependence of longevity on stem cell function is a novel, major focus in aging research. Research conducted by this project has provided evidence that p66Shc affects the regenerative and differentiation potentials of stem cells. By investigating the molecular mechanisms of these effects, and the influence of dietary conditions (calone restriction, high-fat diet), the aim of Project 3 is to get insight into and possibly exploit the routes of life-extending environmental factors.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (02))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
United States
Zip Code
McMackin, Marissa Z; Henderson, Chelsea K; Cortopassi, Gino A (2017) Neurobehavioral deficits in the KIKO mouse model of Friedreich's ataxia. Behav Brain Res 316:183-188
Granatiero, Veronica; Gherardi, Gaia; Vianello, Matteo et al. (2017) Role of p66shc in skeletal muscle function. Sci Rep 7:6283
Song, Lanying; Yu, Alfred; Murray, Karl et al. (2017) Bipolar cell reduction precedes retinal ganglion neuron loss in a complex 1 knockout mouse model. Brain Res 1657:232-244
Taylor, Sandra L; Ruhaak, L Renee; Weiss, Robert H et al. (2017) Multivariate two-part statistics for analysis of correlated mass spectrometry data from multiple biological specimens. Bioinformatics 33:17-25
Roberts, Megan N; Wallace, Marita A; Tomilov, Alexey A et al. (2017) A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab 26:539-546.e5
Baldassini, W A; Ramsey, J J; Hagopian, K et al. (2017) The influence of Shc proteins and high-fat diet on energy metabolism of mice. Cell Biochem Funct 35:527-537
Taylor, Sandra L; Ruhaak, L Renee; Kelly, Karen et al. (2017) Effects of imputation on correlation: implications for analysis of mass spectrometry data from multiple biological matrices. Brief Bioinform 18:312-320
Datta, Sandipan; Baudouin, Christophe; Brignole-Baudouin, Francoise et al. (2017) The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells. Invest Ophthalmol Vis Sci 58:2406-2412
Hagopian, Kevork; Kim, Kyoungmi; López-Dominguez, José Alberto et al. (2016) Mice with low levels of Shc proteins display reduced glycolytic and increased gluconeogenic activities in liver. Biochem Biophys Rep 7:273-286
Datta, Sandipan; Tomilov, Alexey; Cortopassi, Gino (2016) Identification of small molecules that improve ATP synthesis defects conferred by Leber's hereditary optic neuropathy mutations. Mitochondrion 30:177-86

Showing the most recent 10 out of 95 publications