Dr. Seth Karp is an instructor in surgery and senior fellow in transplantation at Johns Hopkins Hospital. His goal is to become an independent investigator in liver development and regeneration and contribute to the treatment of end stage liver disease. To achieve this, he will be working in the laboratory of Dr. Se-Jin Lee, which has expertise in liver development, regeneration, and molecular embryology, the resources Dr. Karp will need to reach his goals. To this point, Dr. Karp has training in developmental and molecular biology, but requires additional training specific to the liver. The current project is divided into two parts. The first examines the effect of long term modulation of activin signaling on liver mass and regeneration. Transient blockade of activin signaling increases liver mass and speeds regeneration, but long term effects of modulating activin siganaling have not been addressed. This leaves unanswered whether activin signaling is the primary determinant of either process, or if this pathway plays a secondary role under the control of another genetic pathway. To address this question, an inducible bigenic system will be used to block activin signaling over long periods of time. Livers will be examined with regard to mass and regenerative capacity. The molecular pathways influenced by this modulation will be dissected using serial analysis of gene expression (SAGE) technology. This will provide quantitative information on which genes are influenced by blockade of activin signaling, and help determine if activin is a primary regulator of liver size and regeneration or a downstream effector of a pathway more fundamental in regulating liver mass and regeneration. The second phase of the project relies on the hypothesis that there is considerable overlap in the genetic program that guides liver development and that which drives regeneration. Using SAGE, libraries will be made from regenerating liver and developing liver. This will define two interesting classes of genes: 1) Genes highly expressed in developing liver but not the regenerating liver. These are likely important for hepatocyte specification and differentiation. 2) Genes highly expressed in the developing liver and either up or downregulated in the regenerating liver. These are likely critical for hepatocyte proliferation. These genes will be screened using northern and in situ hybridization, and investigated using overexpression and targeted deletion.
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