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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG025532-07
Application #
8589546
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2)
Project Start
Project End
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
7
Fiscal Year
2014
Total Cost
$200,855
Indirect Cost
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Granatiero, Veronica; Patron, Maria; Tosatto, Anna et al. (2014) Using targeted variants of aequorin to measure Ca2+ levels in intracellular organelles. Cold Spring Harb Protoc 2014:86-93
Chen, Y; Hagopian, K; Bibus, D et al. (2014) The influence of dietary lipid composition on skeletal muscle mitochondria from mice following eight months of calorie restriction. Physiol Res 63:57-71
Tomilov, Alexey; Bettaieb, Ahmed; Kim, Kyoungmi et al. (2014) Shc depletion stimulates brown fat activity in vivo and in vitro. Aging Cell 13:1049-58
Patron, Maria; Checchetto, Vanessa; Raffaello, Anna et al. (2014) MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell 53:726-37
Sahdeo, Sunil; Tomilov, Alexey; Komachi, Kelly et al. (2014) High-throughput screening of FDA-approved drugs using oxygen biosensor plates reveals secondary mitofunctional effects. Mitochondrion 17:116-25
Logan, Clare V; Szabadkai, Gyorgy; Sharpe, Jenny A et al. (2014) Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nat Genet 46:188-93
Granatiero, Veronica; Patron, Maria; Tosatto, Anna et al. (2014) The use of aequorin and its variants for Ca2+ measurements. Cold Spring Harb Protoc 2014:9-16
Stern, Jennifer H; Kim, Kyoungmi; Ramsey, Jon J (2014) The influence of shc proteins on the whole body energetic response to calorie restriction initiated in 3-month-old mice. ISRN Nutr 2014:562075
Bock, Fabian; Shahzad, Khurrum; Wang, Hongjie et al. (2013) Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proc Natl Acad Sci U S A 110:648-53
Chen, Yana; Hagopian, Kevork; Bibus, Douglas et al. (2013) The influence of dietary lipid composition on liver mitochondria from mice following 1 month of calorie restriction. Biosci Rep 33:83-95

Showing the most recent 10 out of 58 publications