Research interests: Research in my laboratory is geared towards studying medically relevant aspects of digestive organ development.
Keywords: Zebrafish and mouse genetics, developmental biology, cancer, chemical genetics
Research details: Using the zebrafish system, we have applied genetics, gene targeting methodologies and pharmacological analyses to questions pertaining to growth, differentiation and survival of progenitor cells in the intestine, liver and pancreas. Through the positional cloning of zebrafish mutants our studies have led us in a number of directions.
Maintenance of Tissue Architecture
We have shown that a recessive mutation that disrupts the normal regulation of smooth muscle myosin in the intestine drives adjacent epithelial cells to invade the tissue stroma. The invasive cells form matrix degrading invadopodia on their basal cell membrane in response to a physical signal from the adjacent smooth muscle cells, thus providing novel insights into the mechanism of invadopodia formation. Importantly, we have also shown that the myosin mutation sensitizes heterozygous mutant epithelial cells to become invasive in response to oxidative stress. This work has direct relevance to cancer invasion and metastases, particularly how some individuals may have a heritable predisposition to these phenomena. We are now working with mice that carry the identical smooth muscle myosin mutation so we can gauge its effects in colorectal cancer models.
Mechanisms of Bile Duct Development
We have generated zebrafish models of congenital and heritable biliary diseases such as infantile biliary atresia (BA), Alagille syndrome, the ARC syndrome and the rare disorder, North American Indian Childhood Cirrhosis. Most recently we used the zebrafish to identify a novel plant isoflavone that is responsible for epidemic biliary atresia in livestock. This naturally occurring BA model closely will now provide novel mechanistic insights into this enimagtic disorder, which is the most common indication for liver transplantation in the pediatric population.
Intestinal Epithelial Homeostasis
Through mutagenesis we have identified a role for the nuclear pore associated protein Elys in the maintenance of genome stability during DNA replication. Our studies indicate that the Elys protein performs this function independently of its role in driving nuclear pore reassembly. We are using zebrafish and mouse models to further analyze Elys. We have also identified an role for RNA Pol III transcription in epithelial maintenance and have established collaborations to examine this role in mouse models (Kaestner lab).
We are using the zebrafish in chemical genetic screens designed to identify compounds that modulate intestinal lipid absorption and intestinal motility.
Rotation projects for all of these research areas are available.
Current lab personnel:
Xiao Zhao, M.D. - Post-Doctoral Researcher
Benjamin Wilkins, M.D., Ph.D. - Post-Doctoral Researcher
Zev Einhorn, Ph.D. - Post-Doctoral Researcher
Joshua Abrams - Graduate student
Jie He, M.D. - Research Specialist
Mani Muthumani - Research Specialist
Kristin Lorent, Ph.D. - Senior Research Associate
Weilong Gong, Ph.D. - Research Specialist
Gastroenterology and Hepatology.
Valvezan AJ, Huang J, Lengner CJ, Pack M, and Klein PS: Oncogenic mutations in Adenomatous Polyposis Coli (Apc) activate mechanistic Target of Rapamycin Complex 1 (mTORC1). Disease Models and Mechanisms 2013.
Wilkins BJ, Lorent K, Matthews RP, and Pack M: p53-mediated biliary defects caused by knockdown of cirh1a, the zebrafish homolog of the gene responsible for North American Indian Childhood Cirrhosis. PLoS One 2013.
Walters JA, Anderson JL, Bittman R, Pack M and Farber SA: Visualization of lipid metabolism in the larval zebrafish intestine reveals a relationship between NPC1L1 mediated cholesterol uptake and dietary fatty acids. Chemistry and Biology 19(7)(913-25), June 2012.
Abrams J, Davuluri G, Seiler C, Pack M: Smooth muscle caldesmon modulates peristalsis in the wild type and non-innervated zebrafish intestine. Neurogastroenterology and Motililty 24(3): 288-99, 2012.
Seiler C, Davuluri G, Abrams J, Byfield FJ, Janye PA and Pack M: Smooth muscle tension induces invasive remodeling of the zebrafish intestine. PLoS Biology 10(9)(:e1001385), 2012.
Gao N, Davuluri G, Gong W, Seiler C, Furth EE, Kaestner K and Pack M : The Nuclear Pore Complex Proetin Elys is Required for Genome Stability in Mouse Intestinal Epithelial Progenitor Cells
Gastroenterology 140(5): 1547-1555, 2011.
Matthews RP, Eua Claire SF, Mungier M, Lorent K, Cui Shuang, Zhang Z, Russo P and Pack M : DNA Hypomethylation Causes Bile Duct Injury in Zebrafish and Is a Distinguishing Feature of Infantile Biliary Atresia
Hepatology 3(3): 905-14, 2011.
Davulri G, Seiler C, Abrams J, Soriano AJ and Pack M : Differential Effects of Thin and Thick Filament Disruption on Zebrafish Smooth Muscle Regulatory Proteins. Neurogastroenterology and Motility 22(10), 2010.
Lorent K, Moore JC, Siekmann AF, Lawson N, Pack M. : Reiterative use of the notch signal during zebrafish intrahepatic biliary development. Developmental Dynamics 239(3): 855-864, 2010.
Matthews RP, Lorent K, Mañoral-Mobias R, Huang Y, Gong W, Murray IV, Blair IA, Pack M.: TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase. Development 136(5): 865-75, 2009.
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Last updated: 10/16/2013
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