The major portion of this proposal involves the in-depth examination of factors that affect the ability of liver tissue to regenerate after live donor hepatectomy or receipt of a partial liver allograft in a living donor liver transplant (LDLT). In animal models, the A20 gene complex has been shown to be involved in hepatic regeneration after lethal hepatectomy, and in humans, polymorphism in A20 have been identified as susceptibility loci for several inflammatory and autoimmune diseases. These studies will determine if A20 polymorphism and level of expression in donor liver may serve as reliable prognostic markers for successful LDLT. The following studies will be performed: 1) A20 polymorphisms in LDLT donors will be probed for using single nucleotide polymorphisms using donor peripheral blood cells;2) Pre- and post-perfusion liver biopsies will be obtained at the time of transplant and whenever required by clinical situation. A20 mRNA will be determined by quantitative PCR, its cellular distribution will be determined by immunohistochemistry, and levels of priming cytokines and growth factors will be measured;3) Biological and molecular markers will be examined in LDLT donor and recipients on days 1, 3, 5, and 7 post-transplantation/donation and whenever readmitted to hospital;4) Data will be correlated with clinical course and hepatic regeneration as determined by MeVis reconstruction of volumetric CT examination.
The second aim will investigate the role of portal hypertension in the development of small for size syndrome after LDLT. The incidence will be determined by direct measurement of portal pressure and procedures to reduce pressures will be investigated. Outcomes including development of small for size syndrome, hepatic regeneration, and adverse outcomes including death and need for re-transplantation will be analyzed. The effect of hepatic regeneration on LDLT donors will be examined by comparing results of validated quality of life instruments with CT volumetric determinations of hepatic regeneration at 1, 2, and 5 years after donation. Finally the effect of donor and recipient socioeconomic factors on access to LDLT will be studied.

Public Health Relevance

These studies will integrate the expertise of clinicians, basic scientists, and clinical researchers and have potential to identify A20 based therapies useful for the prevention or treatment of liver graft dysfunction, identify and devise treatment strategies for portal hyperperfusion, identify effect of hepatic regeneration on donor quality of life, and demonstrate socioeconomic factors that enhance or impede access to LDLT.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK085515-04
Application #
8330871
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O2))
Program Officer
Sherker, Averell H
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$121,913
Indirect Cost
$62,926
Name
Lahey Clinic
Department
Type
DUNS #
883850364
City
Burlington
State
MA
Country
United States
Zip Code
01805