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.
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