Cell differentiation is a process in which a precursor cell develops into a new type of cell in response to specific internal or external stimuli. The lon term goal of this proposal is to understand how to control low rates of terminal cell differentiatin such are observed in vivo to maintain tissue size under normal conditions. Adipocyte differentiation, or the conversion of proliferating precursor cells into non-dividing fat cells or adipocytes capable of accumulating lipid, is one of the most accessible experimental systems for investigating terminal differentiation in mammalian cells. Understanding adipogenesis also has great medical relevance since defects in adipogenesis underlie the current worldwide epidemics in obesity, insulin resistance, diabetes, and cardiovascular disease. Computational modeling, quantitative mass spectrometry and single-cell microscopy will be used to identify and understand the system architecture and molecular mechanisms that cells use to have sufficient cell-to-cell variability in protein expression (noise) required to regulate small fractional rates f cell differentiation while at the same time allowing for controlled and stable terminal cell differentiation. The outcome of this work will be a fundamental understanding of the system architecture and molecular mechanisms that can control small fractional differentiation rates, opening up new venues of therapeutic intervention for the defective adipocyte differentiation underlying insulin resistance and type 2 diabetes. The results of this study will likely have broad relevance for all cell differentiation processes and may help in developing novel approaches to restore defective or aging cardiac, neuronal, hematopoietic, and other tissues.

Public Health Relevance

Cell differentiation is a process in which a precursor cell develops into a new type of cell in response to specific internal or external stimuli. The long ter goal of this study is to understand how to control low rates of stable terminal cell differentiatio. The results of this study will likely have broad relevance for all cell differentiation processes ad may help in developing novel approaches to restore defective or aging cardiac, neuronal, hematopoietic, and other tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK101743-03
Application #
9211314
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Sechi, Salvatore
Project Start
2015-02-01
Project End
2018-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$325,012
Indirect Cost
$122,512
Name
Stanford University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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Teruel, Mary N; Gu, Bo; Zhao, Michael L (2015) A dynamic picture of protein behavior in cells. Nat Biotechnol 33:356-7
Ota, Asuka; Kovary, Kyle M; Wu, Olivia H et al. (2015) Using SRM-MS to quantify nuclear protein abundance differences between adipose tissue depots of insulin-resistant mice. J Lipid Res 56:1068-78
Ahrends, Robert; Niewiadomski, Pawel; Teruel, Mary N et al. (2015) Measuring Gli2 Phosphorylation by Selected Reaction Monitoring Mass Spectrometry. Methods Mol Biol 1322:105-23