Professor, Departments of Pathology, Molecular and Human Genetics, and Molecular & Cellular Biology; Program in Cell & Molecular Biology

B.A., University of Colorado, 1964
Ph.D., University of Michigan, 1970
Postdoc, Yale University, 1972

RESEARCH INTERESTS:

Mechanisms of Liver Regeneration and Liver Stem Cell Gene Expression

The liver is capable of regeneration in response to loss of liver mass. The kinetics of cell division after surgical removal of two thirds of the liver has been well documented in young animals. Aging results in a diminished and delayed response of the liver to the proliferative stimulus induced by partial keratectomy. We have begun to characterize the molecular basis for the age associated alteration in the growth response of hepatocytes in old animals to partial hepatectomy (PH). It has been calculated that 70 percent of the hepatocytes in old rats fail to enter DNA synthesis following surgically induced regeneration whereas less than one percent of cells fail to undergo cell division in juvenile animals (Stocker and Heine, 1971).

Definition of the biochemical pathways that are altered in old animals will provide insight to the basis for reduced response in old mice to PH. The cytokine signals for the hepatocyte proliferative response, as measured by activation of transcription factors downstream of cytokine receptor signaling bind their consensus sites with the same kinetics between young and old. Thus we propose that the alterations in response to the proliferation signals may occur in genes that are not regulated by these important proteins and may be efficiently studied by gene expression profiling. We will determine whether some genes/pathways of PH response are differentially expressed in old animals. An alternative, but not mutually exclusive, outcome is that the profile of gene expression is similar between the two ages being compared, but follows different kinetics.

A second area of interest is the definition of the molecular basis for longevity in three different long-lived mouse strains. A single gene mutation in a pituitary-specific transcription factor (Prop-1) leads to increased longevity in mice. The growth hormone releasing hormone receptor deficient mice also result in increased longevity. By comparing the gene expression profiles of these strains with their wild type counterparts and with the other mutant strain, we have identified candidate genes for increased life span. Several pathways are implicated in the extension of life span and we are now pursuing the regulation of xenobiotic metabolism in the long lived strains to understand the molecular mechanisms of the up-regulation of this pathway and to determine whether the elevation of xenobiotic metabolism has a causal effect on life span.

A third area of interest is the characterization of liver stem cells using gene expression profiling. Liver cell populations will be sorted using markers of hematopoietic stem cells and oval cells then tested by transplantation for their capacity to differentiate into hepatocytes and bile duct epithelium. The populations that have pluripotential properties will be characterized by microarray analysis for their patterns of gene expression. One goal will be to identify genes whose protein products may serve as markers for stem cells and that may be used to select the stem cells from a population of multiple cell types. A second goal is to use the gene expression patterns to make predictions about the biology of stem cells.

SELECTED PUBLICATIONS:

1. Singh P, Coskun ZZ, Goode C, Dean A, Thompson-Snipes L, Darlington G (2008). Lymphoid neogenesis and immune infiltration in aged liver. Hepatology 47: 1680-1690.

2. Ochsner SA, Strick-Marchand H, Qiu Q, Venable S, Dean A, Wilde M, Weiss MC, Darlington GJ (2007). Transcriptional profiling of bipotential embryonic liver cells to identify liver progenitor cell surface markers. Stem Cells 25: 2476-2487.

3. Amador-Noguez D, Dean A, Huang W, Setchell K, Moore D, Darlington G (2007). Alterations in xenobiotic metabolism in the long-lived Little mice. Aging Cell. 6: 453-470.

4. Amador-Noguez D, Yogi K, Venable S, Darlington GJ (2004). Gene expression profile of long lived Ames dwarf and little mice. Aging Cell 3: 423-441.

5. Welm AL, Timchenko NA, Ono Y, Sorimachi H, Radomska HS, Tenen DG, Lekstrom-Himes J, Darlington GJ (2002). C/EBPalpha is required for proteolytic cleavage of cyclin A by calpain 3 in myeloid precursor cells. J. Biol. Chem. 277: 33848-33856.

6. Linhart HG, Ishimura-Oka K, DeMayo F, Kibe T, Repka D, Poindexter B, Bick RJ, Darlington GJ (2001). C/EBP is required for differentiation of white, but not brown, adipose tissue. Proc. Natl. Acad. Sci. USA 98: 12532-12537.

7. Welm AL, Mackey SL, Timchenko LT, Darlington GJ, Timchenko NA (2000). Translational induction of liver-enriched transcriptional inhibitory protein during acute phase response leads to repression of CCAAT/enhancer binding protein alpha mRNA. J. Biol. Chem. 275: 27406-27413.

8. Welm AL, Timchenko NA, Darlington GJ (1999). C/EBPalpha regulates generation of C/EBPbeta isoforms through activation of specific proteolytic cleavage. Mol. Cell Biol. 19: 1695-1704.

9. Burgess-Beusse BL, Darlington GJ (1998). C/EBPalpha is critical for the neonatal acute phase response to inflammation. Mol. Cell Biol. 18: 7269-7277.

10. Darlington GJ, Ross S, MacDougald OA (1998). The role of C/EBP genes in adipocyte differentiation. J. Biol. Chem. 273: 30057-30060.

11. Timchenko NA, Wilde M, Nakanishi M, Smith JR, Darlington GJ (1996). CCAAT/enhancer binding protein alpha (C/EBPalpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. Genes Dev. 10: 804-815.

12. Wang ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD, Taylor LR, Wilson, DR, Darlington GJ (1995). Impaired energy homeostatsis in C/EBPalpha knockout mice. Science 269: 1108-1112.

For more publications, see listing on Pub Med.

CONTACT INFORMATION:

Gretchen J. Darlington, Ph.D.
Huffington Center on Aging, N803
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030

Phone: 713-798-1565
Fax: 713-798-4161
E-mail:

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