In MSRB II level A
MJR PTC 100 standard thermocycler; Cepheid Smartcycler (for real-time quantitative PCR); Kodak EDAS 290 imaging system; Fisher Isotemp dual CO2 incubator; Laminar flow hoods, Genesys 8 thermospectrophotometer; IEC CL3R desktop centrifuge; two Dell PC pentium-3 computers with internet access and LAN access to the UMHS system. Electrophoresis and gel apparatus are also set up for both Western and Northern blot analysis. An Ussing chamber apparatus is located in Pediatric Surgery Research space in Mott Children's Hospital.

Alterations in IEL phenotype and function while on TPN

Dr. Teitelbaum's research concerns two areas of nutritional complications of TPN. The first concerns the alteration of the gut-associated lymphoid tissue while on total parenteral nutrition using a mouse model. The second concerns the mechanisms involved in the development of parenteral nutrition-associated cholestasis in this same mouse model.

Alteration in Intraepithelial Lymphocytes with Total Parenteral Nutrition

Collaborators: Hua Yang, M.D., Ph.D.
Funding: NIH and Abbott Laboratories

A number of alterations occur in the intestinal mucosa during the administration of TPN, including a loss of mucosal integrity, a decline in mucosal epithelial growth and absorptive function, and a significant change in the lymphocytes of the mucosal epithelium - the intraepithelial lymphocytes (IEL). Despite the long-standing knowledge of these observed changes, relatively little is known relating to the factors which influence these changes. We have demonstrated several changes in the IEL with TPN administration. In particular, we have shown that the IEL changes its phenotype and cytokine expression without enteral nutrition. These changes, including an increased expression of interferon gamma result in a loss of epithelial barrier function, and an increase in epithelial cell apoptosis via a Fas/FasL pathway. We have additionally shown that the IEL is a rich source of keratinocyte growth factor (KGF). This factor supports epithelial cell growth. We are currently studying what factors induce or reduce the expression of IEL-derived KGF using mouse models of TPN (used to study effects during villus atrophy) and a short bowel syndrome model (used for villus hypertrophy).

Expression of the Multi-Drug Resistant Gene 2 in a Mouse Model of TPN: Relevance to the Development of Parenteral Nutrition-Associated Cholestasis

Collaborators: Yuko Tazuke, M.D.
Funding: Internal

A major adverse consequence of TPN in neonates is the development of parenteral nutrition-associated cholestasis (PNAC). The development of PNAC predisposes neonates to an increased incidence of sepsis, higher mortality rates and the potential to develop irreversible injury to the liver. Recently, a genetic model of cholestasis has been developed in mice by disrupting the multi-drug resistant 2 (mdr2) gene. The mdr2 gene encodes a cell membrane phosphoglycoprotein (P-gp) which is responsible for the secretion of phospholipids across the hepatic canalicula into bile, and has the same function as the human MDR3 gene. Without such a function the bile contains a disproportionately high concentration of hepatotoxic bile acids which results in cholestasis due to sludging and direct injury to the liver. We have demonstrated that administration of TPN results in a down regulation of mdr2 mRNA expression in the liver. We are investigating the role of mdr2 with the administration of TPN.

Environmental Tobacco Smoke and its Effect on Post-operative Recovery Time and Ciliary Beat Frequency in Children Undergoing Laparotomy or Thoracotomy

Collaborators: Robert A. Drongowski, PI Reynolds, and AG Coran
Funding: Research Advisory Committee

Environmental tobacco smoke (ETS) (passive smoking or second-hand-smoke) is deleterious to the health of children and infants. Tobacco smoke can have direct effects on the secretory and transport functions of airway epithelial cells, and is ciliary toxic. Ciliary beat frequency (CBF) has been found to be decreased in smokers compared to non-smokers. These observations may help explain why children of smokers have increased respiratory complications than children of non-smokers. This mechanism appears to be mediated via a direct physiological effect of tobacco smoke upon secretory and transport functions in the cilia of the respiratory tract. We plan to measure CBF in patients undergoing laparotomy or thoracotomy and correlate urinary cotinine levels (measure of nicotine exposure) with CBF in children.