C/EBPalpha has an important role in regulating energy metabolism, in the differentiation and maturation of lung and adipose tissues, and in the acute phase or inflammatory response. During the last grant period the applicant has made a C/EBPalpha knockout mouse mutant. Most of the homozygous mutants die prenatally, exhibiting many features of prematurity, including hypoglycemia, inadequate glycogen stores, no fat accumulation and immature lungs. Of special interest, although the mutant animals have brown adipose tissues, they fail to develop mature white adipose tissue, suggesting that C/EBPa is required for same final step in white adipose tissue maturation.
Her specific aim 1 is to clone adipose-specific genes that are differentially expressed in normal and C/EBPa knockout animals. Enzymatic Degrading Subtraction, or Differential Display methods will be used to capture C/EBPa-regulated loci that are essential in adipose tissue differentiation and maturation.
Her second aim i s to examine C/EBPa-dependent gene expression in a two gene model for conditional expression of C/EBP. The vast majority of C/EBPa knockout animals die within a day of birth from hypoglycemia secondary to a failure to store glycogen in the liver. To overcome this problem, the applicant proposes to express a C/EBPa transgene conditionally in the liver.
Her specific aim 3 is to identify the minimal region of the C/EBPa gene that governs its adipose tissue-specific expression in vivo with the help of a transgenic mouse system using a CAT reporter gene. The resulting information would be an initial step in developing strategies to activate C/EBPa prematurely or to regulate its expression in adipose tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045285-07
Application #
2905492
Study Section
Metabolism Study Section (MET)
Program Officer
Haft, Carol Renfrew
Project Start
1993-05-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Linhart, H G; Ishimura-Oka, K; DeMayo, F et al. (2001) C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. Proc Natl Acad Sci U S A 98:12532-7
Timchenko, N A; Wilde, M; Iakova, P et al. (1999) E2F/p107 and E2F/p130 complexes are regulated by C/EBPalpha in 3T3-L1 adipocytes. Nucleic Acids Res 27:3621-30
Burgess-Beusse, B L; Timchenko, N A; Darlington, G J (1999) CCAAT/enhancer binding protein alpha (C/EBPalpha) is an important mediator of mouse C/EBPbeta protein isoform production. Hepatology 29:597-601
Wu, Z; Rosen, E D; Brun, R et al. (1999) Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell 3:151-8
Timchenko, N A; Wilde, M; Kosai, K I et al. (1998) Regenerating livers of old rats contain high levels of C/EBPalpha that correlate with altered expression of cell cycle associated proteins. Nucleic Acids Res 26:3293-9
Oesterreicher, T J; Leeper, L L; Finegold, M J et al. (1998) Intestinal maturation in mice lacking CCAAT/enhancer-binding protein alpha (C/EPBalpha). Biochem J 330 ( Pt 3):1165-71
Kimura, T; Christoffels, V M; Chowdhury, S et al. (1998) Hypoglycemia-associated hyperammonemia caused by impaired expression of ornithine cycle enzyme genes in C/EBPalpha knockout mice. J Biol Chem 273:27505-10
Darlington, G J; Ross, S E; MacDougald, O A (1998) The role of C/EBP genes in adipocyte differentiation. J Biol Chem 273:30057-60
Soriano, H E; Kang, D C; Finegold, M J et al. (1998) Lack of C/EBP alpha gene expression results in increased DNA synthesis and an increased frequency of immortalization of freshly isolated mice [correction of rat] hepatocytes. Hepatology 27:392-401
Burgess-Beusse, B L; Darlington, G J (1998) C/EBPalpha is critical for the neonatal acute-phase response to inflammation. Mol Cell Biol 18:7269-77

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