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.
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.
|Tosatto, Anna; Sommaggio, Roberta; Kummerow, Carsten et al. (2016) The mitochondrial calcium uniporter regulates breast cancer progression via HIF-1Î±. EMBO Mol Med 8:569-85|
|Datta, Sandipan; Sahdeo, Sunil; Gray, Jennifer A et al. (2016) A high-throughput screen for mitochondrial function reveals known and novel mitochondrial toxicants in a library of environmental agents. Mitochondrion 31:79-83|
|Taylor, Sandra L; Ruhaak, L Renee; Kelly, Karen et al. (2016) Effects of imputation on correlation: implications for analysis of mass spectrometry data from multiple biological matrices. Brief Bioinform :|
|Tian, Jijing; Yang, Guoxiang; Chen, Huan-Yuan et al. (2016) Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J 30:4202-4213|
|Raffaello, Anna; Mammucari, Cristina; Gherardi, Gaia et al. (2016) Calcium at the Center of Cell Signaling: Interplay between Endoplasmic Reticulum, Mitochondria, and Lysosomes. Trends Biochem Sci 41:1035-1049|
|Tomilov, Alexey; Tomilova, Natalia; Shan, Yuxi et al. (2016) p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria. J Biol Chem 291:12575-85|
|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|
|Shen, Yan; McMackin, Marissa Z; Shan, Yuxi et al. (2016) Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34. PLoS One 11:e0151026|
|Taylor, Sandra L; Ruhaak, L Renee; Weiss, Robert H et al. (2016) Multivariate two-part statistics for analysis of correlated mass spectrometry data from multiple biological specimens. Bioinformatics :|
|Song, Lanying; Cortopassi, Gino (2015) Mitochondrial complex I defects increase ubiquitin in substantia nigra. Brain Res 1594:82-91|
Showing the most recent 10 out of 88 publications