Alagille Syndrome — New Research, New Hope

Chair

Jagged signaling in biliary development, disease, and regeneration

Assistant Professor, Human Genetics Program
Sanford Burnham Prebys Medical Discovery Institute

Dr. Dong received his Biology Bachelor of Science degree in 1996 from the University of California, Irvine, where he was involved in molecular evolution and limb regeneration research. He earned his Ph.D. in Cell and Molecular Biology investigating master control genes and tissue lineage regulation at the University of Wisconsin, Madison in 2002. He did his postdoctoral research at the University of California, San Francisco, where he focused on developmental genetics of the liver and pancreas. Dr. Dong was recruited as an Assistant Professor to Sanford Burnham Prebys Medical Discovery Institute in 2008. He is a recipient of the NIH Director’s New Innovator Award, which funds the development of in vivo lineage conversion technologies to generate replacement cells and organs within a living vertebrate. His vision is to make in vivo lineage reprogramming a practical strategy for regenerative medicine. His lab’s underlying approach is to gain basic and biomedical insight through rigorous investigation of the genetic mechanisms governing organogenesis, diseases, and cell lineage commitment/conversion. They have discovered multiple genes critical for lineage specification of liver and pancreas progenitors and have developed several in vivo models for diseases such as early onset diabetes and Alagille Syndrome. Most recently, they discovered a way to reprogram differentiated cells to adopt a completely unrelated identity, without having to remove them from the body. Dr. Dong’s ultimate goal is to determine how gene function can be manipulated to help cure diseases and advance regenerative medicine.

Co-Chair

Hepatocyte plasticity: Metaplasia or transdifferentiation?

Professor, Department of Surgery, Division of Transplantation
Associate Director, Liver Center
University of California San Francisco

Holger Willenbring’s laboratory in the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California San Francisco works on developing the scientific basis for new therapies for liver diseases. Holger Willenbring received his degrees from the Medical University Lübeck, Germany and did a residency in pediatrics at the University of Münster, Germany. Prompted by his clinical experience, he did postdoctoral research exploring alternative cell sources for liver cell therapy in the laboratory of Markus Grompe at Oregon Health & Science University. In addition to generating transplantable, fully functional human hepatocytes from readily accessible, autologous cells, his laboratory is investigating the cell and molecular biology of liver regeneration, including transdifferentiation of hepatocytes into cholangiocytes.

Speakers

Investigating Notch control of development using high-throughput in utero gene manipulation

Karolinska Institutet, Stockholm, Sweden

Emma R. Andersson is an Assistant Professor at the Karolinska Institute, Stockholm. Dr Andersson has a long-standing interest in genetic disease and control of regeneration. As a Ph.D. student with Ernest Arenas at the Karolinska Institute, she elucidated a role for Wnt signaling in the morphogenesis and differentiation of the embryonic midbrain and dopaminergic neurons therein. During her postdoctoral studies with Urban Lendahl at the Karolinska Institute, her work focused on the role of Notch signaling in murine development and human congenital disease. She performed guest research in the laboratories of Professors Elaine Fuchs and Mary E Hatten (Rockefeller University) to further develop the technique of ultrasound-guided nano-injection of developing mouse embryos, to achieve gene targeting in a versatile and rapid manner in vivo. Currently, her research focus is on the genetic and mechanistic basis of Alagille Syndrome, a multi-organ disease caused by defects in Notch signaling, and the development of techniques to manipulate gene expression in vivo in mammalian systems, in a high-throughput fashion.

Realizing realtime results through rapid sequencing leads to timely treatment in children with cholestasis

Medical Director, Institute for Genomic Medicine
Rady Children’s Hospital - San Diego

Dr. David Dimmock is a nationally-renowned expert on the field of clinical genomic medicine.  Since becoming the Medical Director of the newly formed Rady Children’s Hospital Institute for Genomic Medicine in San Diego California he has been involved in the deployment of rapid genomic sequencing for infants in the ICUs.

He was the clinician primarily responsible for the first use of exome sequencing to change the medical management of a child. This case was the subject of Pulitzer Prize winning articles and the book, One in a Billion: The Story of Nic Volker and the Dawn of Genomic Medicine.

Subsequently, in 2010, he was a leader of the team that deployed the first clinical end-to-end whole genome sequencing test. This solution included patient counselling and consent, clinical laboratory testing, data analysis, data return.

His basic science lab has been actively involved in understanding the genetic basis for neonatal liver disease. More recently working on a potential therapy for a mitochondrial liver disease.

Before joining Rady Children’s, Dr. Dimmock’s clinical practice focused on the diagnosis of heritable disorders in children and adults and the long term care of patients with mitochondrial and metabolic disorders. He has been the principal investigator for multiple industry sponsored studies evaluating novel therapeutics for these disorders.

Cell diversity in liver regeneration

Assistant Professor
Cancer Biology
Fox Chase Cancer Center

 

Video
Dr. Joan Font-Burgada received his Ph.D. degree in Genetics from the University of Barcelona, where he studied the histone code using Drosophila HP1 proteins as a model. For his postdoctoral studies, he moved to Michael Karin’s lab at UCSD and became interested in liver regeneration and cancer development. As a CIRM postdoctoral scholar, he identified a new subpopulation of hepatocytes, Hybrid Hepatocytes (HybHP), with a pivotal role in the repair of the injured liver. He recently obtained an NCI K99/R00 award to generate mouse models that replicate the complexity of human hepatocellular carcinoma genetics. He is starting his own laboratory in 2017 as an Assistant Professor at the Fox Chase Cancer Center in Philadelphia to delve into the mechanisms of liver regeneration and liver cancer development.

Making ducts from hepatocytes

Director, Oregon Stem Cell Center 
Director, Pape Family Pediatric Research Institute 
Ray Hickey Chair, Oregon Health & Science University

Dr. Grompe received his medical degree (Dr. med.) in 1983 at the University of Ulm Medical School in Germany. His interest in Human Genetics started with a one year research project abroad during medical school. From 1984-1987 Dr. Grompe was trained in Pediatrics at Oregon Health Sciences University in Portland, Oregon, USA and then moved to Baylor College of Medicine in Houston, Texas. There he was a fellow sponsored by the Pediatric Scientist Training Program in the Institute for Molecular Genetics from 1987-1991 and worked on gene therapy for inherited diseases, particularly metabolic liver disorders. In 1991, Dr. Grompe joined the faculty at Oregon Health & Sciences University and he is currently Professor in the Departments of Pediatrics and Molecular and Medical Genetics. 

In 2002 he received the most prestigious award for Pediatric Research in the United States, the E. Mead Johnson Award. In same year he was given the Merit Award of the Fanconi Anemia Research Foundation. In 2007 he was chosen for the Oregon Medical Research Foundation Discovery Award. 

Dr. Grompe is involved in the clinical care of patients with genetic diseases as well as scientific investigation. In 2004 he became the first director of the newly founded Oregon Stem Cell Center. Since 2008 he is the holder of the Ray Hickey Chair and the first Director of the Papé Family Pediatric Research Institute.

His research has focussed on the use of in vivo selection to enhance gene and cell therapy, particularly stem cell therapy. The two model diseases being studied are hereditary tyrosinemia type 1, a childhood liver disease and Fanconi Anemia (FA), a blood disorder. In 1996, his laboratory showed that gene therapy in combination in vivo selection could be used to replace > 90% of cells in a diseased mouse liver. Since then, his work has focussed on the biology of intra- and extrahepatic liver stem cells and their use in therapeutic liver repopulation. His group developed a patented method to replace the cells of mouse livers with human hepatocytes. Recently, he discovered that hepatocytes are subject to the ploidy conveyor, making them genetically heterogeneous and highly aneuploid.

The Fanconi anemia pathway is involved in the maintenance of genomic stability and stem cell integrity in mammals. The Grompe Lab cloned a novel Fanconi Anemia gene, FANCD2, which has been shown to link the Fanconi Anemia pathway to BRCA1 and BRCA2, genes involved in familial breast cancer. Preclinical gene therapy experiments in murine models of FA have been used to demonstrate in vivo selection at the level of hematopoietic stem cells. Recently, the Grompe lab has discovered small molecules to prevent solid tumors in this disease.

Dr. Grompe holds several patents and is the Founder of Yecuris, Inc. a Portland-based start-up company dedicated to generating animals with humanized livers for life science research and cell therapy. He also co-founded the DNA Repair company, based in Boston, MA. 

Molecular factors regulating hepatic cell identity

Associate Professor, Division of Gastroenterology, Hepatology & Nutrition, 
Division of Developmental Biology
Cincinnati Children’s Hospital Medical Center

Stacey S. Huppert, Ph.D., is an Associate Professor of Gastroenterology, Hepatology and Nutrition at Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine. Dr. Huppert’s research program explores how intercellular signaling pathways are integrated to coordinate cell fate decisions and allocate cell types during both organogenesis and regeneration. She is specifically focused on the therapeutic potential of differentiated hepatocytes to augment or regenerate insufficient intrahepatic bile duct systems. Dr. Huppert’s work has established a three-dimensional blueprint for the formation of intrahepatic bile duct architecture which has earned the cover of Hepatology twice. She is involved in a multidisciplinary group, Solving Organ Shortage, whose mission is to advance research initiatives for regenerating liver or engineering livers for human transplant. Her collaborative efforts bridging investigators from multiple disciplines to tackle diseases due to bile duct insufficiency has been featured. Notch signaling is a specific focus of Dr. Huppert and one pathway that holds promise as a therapeutic target for treatment of many cancers and congenital diseases. Her work, demonstrating that proper cell fate decisions stem from Notch signaling imparting feedback regulation of ligand and receptor asymmetric expression, continues to be a central concept in canonical Notch signaling. Dr. Huppert combines cellular and biochemical screens with advanced methods to quantify three-dimensional changes of in vivo vascular and epithelial structures enabling the search for targets that fine-tune regulation of Notch pathway activity.

Modeling Jag1 haploinsufficiency in mice

Associate Professor
Department of Molecular & Human Genetics
Baylor College of Medicine 

Hamed Jafar-Nejad’s group is interested in the roles of glycosylation and deglycosylation in the regulation of animal development and in human disease pathogenesis. He received his MD from Tehran University of Medical Sciences and learned basic molecular biology techniques in a research institute in Iran. He spent one year in the Neuroscience Research Institute at the University of Ottawa, where he studied the transcriptional regulation of a serotonin receptor implicated in mood disorders. He then moved to Houston and performed his postdoctoral training in the area of Notch signaling and Drosophila neurogenesis with Dr. Hugo Bellen at Baylor College of Medicine. In December 2006, he joined the faculty at the University of Texas Health Science Center at Houston, focusing on a glycosyltransferase called Rumi, which they had identified in Drosophila as a key regulator of the Notch signaling pathway. In 2012, he was recruited back to Baylor, where his group continues their studies on the role of glycosylation in animal development. In recent years, Jafar-Nejad laboratory has devoted significant effort to understanding the function of human rare disease genes in animal development. In one project, the lab has established a mouse model for Alagille syndrome and has identified Rumi (Poglut1) as a dominant genetic suppressor of the Alagille biliary phenotypes in the mouse. In another project, they are using Drosophila to understand the developmental roles of a deglycosylation enzyme called N-glycanase 1 (NGLY1), mutations in which cause a multi-system developmental disorder called NGLY1 deficiency. It is hoped that these collaborative studies will shed light on the pathophysiology of these two diseases and will help identify new therapeutic approaches for them.

High-dimensionality perturbation methods towards control of cell fate and implications for rare disease research

Associate Staff, Stem Cell Biology and Regenerative Medicine
Cleveland Clinic
Lerner Research Institute

Jan Jensen obtained his PhD from U. Copenhagen in 1998, and has  been an academic researcher in the U.S. since 2001. He is the Eddie J. Brandon endowed chair of He is a molecular developmental biologist with particular expertise in development of pancreas, stomach, lung and gut, and more recently, directed differentiation of pluripotent stem cells. His main personal research interest is the development of pancreatic insulin producing cells for cell based therapy of Diabetes. He has developed specific computer resources and databases focused on pancreatic development. Dr. Jensen in a currently a project co-director in a consortium effort to define culture conditions for all cells of the renal lineages (www.rebuildingakidney.org). Recently, he has designed an integrated system for Systems Developmental Biology, which is unique in its ability to identify controlling inputs, additive interactions, their strength and statistical confidence in advanced cell culture and differentiation. He is a founder of Trailhead Biosystems, Inc.

The liver disease in Alagille syndrome: Pathology, clinical insights and the unknowns

Staff Physician, Division of Gastroenterology, Hepatology & Nutrition
The Hospital for Sick Children
Associate Scientist, Research Institute & Associate Professor, University of Toronto

Current position as an Associate Professor of Pediatrics at University of Toronto; Faculty member of the Division of Gastroenterology, Hepatology and Nutrition at the Hospital for Sick Children, Toronto; Associate Scientist at the SickKids Research Institute. 

Binita was educated at Cambridge University in England and trained at several London hospitals, including Kings College Hospital. She moved to the Children’s Hospital of Philadelphia in 2000 and completed her fellowship in GI, Hepatology and Nutrition. She joined the faculty in 2006 and developed a strong interest in cholestatic liver disease, specifically Alagille syndrome. She joined the faculty at the Hospital for Sick Children in 2009 as a Hepatologist and Clinician-Investigator continuing to work on biliary diseases and utilizing stem cell biology to develop disease models.

Panel Session Chair

President and CEO
Amplyx

Ciara Kennedy, Ph.D., is president and CEO of Amplyx Pharmaceuticals, Inc. Initially, Ciara Kennedy was appointed chief operating officer of Amplyx in October 2015, following a successful, $50 million Series B financing. Prior to joining Amplyx, Dr. Kennedy served as chief operating officer at Lumena Pharmaceuticals until the company was acquired by Shire Pharmaceuticals in June 2014; she remained with Shire for one year post-acquisition as vice president and head of the cholestatic liver disease program. As COO of Lumena, Dr. Kennedy played a critical role in the development of assets licensed from Pfizer and Sanofi, raising $78M from venture capital to fund operations and preparing to take the company public. Ciara has a proven track record of delivering significant results and advancing therapeutic and diagnostic programs across multiple therapeutic areas and stages of development in the biotechnology industry. Prior to Lumena, she was vice president of operations and senior director of strategy and corporate development at Cypress Bioscience Inc., where she played a key role in obtaining FDA approval for Savella, a therapy for fibromyalgia, and also oversaw corporate acquisitions and in-licensing of several clinical assets. Previously, Dr. Kennedy held several positions in the program and alliance department of Biogen Idec, managing projects spanning the drug discovery and development continuum. Dr. Kennedy received her doctorate at the Queen’s University of Belfast, Northern Ireland, and continued her research in the field of apoptotic proteases at the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California. In 2004, she became a member of the inaugural class of the Rady School of Management at University of California, San Diego. She graduated with a Masters of Business Administration in 2006.

Notch signaling in nephron segmentation

William K. Schubert Professor of Pediatrics
Director, Division of Developmental Biology
Cincinnati Children’s Hospital Medical Center 

Dr. Kopan has carried out seminal work in the field of Notch biology. This work has, and continues to have, an enormous impact on our understanding of normal tissue development and renewal, developmental syndroms, Alzheimer’s disease and cancer-related research. In deciphering the mechanism of Notch activation and demonstrating the use of inhibitors to modulate Notch activity, Dr. Kopan’s work laid the groundwork for the therapeutic use of g-secretase inhibitors in the treatment of cancers, currently in clinical trials. His current interests in organogenesis are focused on two modular organs- skin and kidney- in which his group is trying to understand how interplay among organs and the immune system shapes systemic responses to injury results and how Notch receptor activation contributes to distant programs in different organs. To that end Dr. Kopan is active in developing novel assays using these technologies to understand integration of Notch with other signaling pathways. Dr Kopan’s work resulted in 138 scientific articles, is the co-inventor of 1 patent, and is a sought-after consultant to the pharmaceutical industry.

My ALGS Journey

Member, Board of Directors
Alagille Syndrome Alliance (ALGSA) 

Video
Anna Laurent is a 21-year-old, college senior majoring in Social Work at Murray State University. Born and raised on a family farm in Princeton, Kentucky, she has been advocating for rare diseases for many years. 

In celebration of Rare Disease Day, she created the campaign Rare Acts of Kindness, to raise awareness while shedding a positive light on those affected by rare disease, In March 2015, she co-founded a Facebook support group for teens and young adults with Alagille Syndrome (ALGS). It has grown to include 30 members with eight countries represented, including India, Guatemala, Australia and Ireland. In August 2015, Anna became the first Junior Board Member of the Alagille Syndrome Alliance (ALGSA), an international non-profit network providing resources, support and advocacy for those affected by ALGS. 

In this position, Anna assisted in updating the Classroom Booklet, a publication of the ALGSA, which serves as a guide for teachers and parents of students with ALGS. She was the keynote speaker at the International Symposium on Alagille Syndrome and served as a moderator and panelist throughout the conference. She updated the childcare program for this symposium and created Camp Alagille, a program for the kids to experience camp activities designed to fit the unique limitations of their conditions without holding them back. 

In August 2016, Anna became a full Board Member of the ALGSA. She plans to continue advocating for those with rare diseases and to use her future Social Work Degree to work in a children’s hospital as a medical social worker. 

Alagille syndrome – life on the jagged edge

Executive Director and Founder
Alagille Syndrome Alliance (ALGSA) 

Cindy D Luxhoj is an energetic and driven mother of three young adults, and Executive Director of the Alagille Syndrome Alliance (ALGSA). When her first child, Alaina, was born in 1990 and diagnosed with Alagille Syndrome (ALGS) at three months of age, Cindy’s A-type personality led her on a quest for information about this rare genetic disease and, when Alaina was three years old, to founding the ALGSA. During her tenure as President and CEO, Cindy dedicated her every available volunteer hour to helping families cope with the daily challenges of this disease. While waiting for a liver transplant in January 2015, Alaina lost her 24-year battle with ALGS and now lives on in the memory of all the ALGS Warriors who loved and admired her. In January 2016, Cindy was hired as Executive Director of the ALGSA and now has the distinct pleasure of being full-time staff for the organization she created and has nurtured for 22 years. When she is not working from her office in Oregon, Cindy is travelling throughout the United States building awareness, educating others about ALGS, and advocating for research and new treatments. In her free time, Cindy enjoys painting, reading, socializing with friends, working out at the local gym, and hiking the beautiful Pacific Northwest. She looks forward to supporting her twin 20-year-old sons as they discover the joys and challenges of college and beyond, and carrying on Alaina’s legacy in the ALGS community. 

Notch signaling in organogenesis and vascular homeostasis

Postdoctoral Scholar, Lab of Luisa Iruela-Arispe, PhD 
University of California, Los Angeles 

Julia J. Mack received her Ph.D. in Chemistry from the University of California, Los Angeles. Her research experience has centered on the development of materials and their interface with cells for the purposes of tissue regeneration. Her doctorate dissertation focused on the synthesis of carbon nanomaterials and their applications in functional composites. In 2004 she was recruited by Teledyne Scientific to join their Composite Materials group where she designed novel composite materials for a variety of applications. Collaborating with bioengineers sparked an interest into understanding the biology behind tissue regeneration and development. Therefore, in 2011 she joined Professor Luisa Iruela-Arispe's laboratory in the Department of Molecular, Cell and Developmental Biology at the University of California, Los Angeles as a Postdoctoral Fellow to design materials to study vasculogenesis in 3D. Her research has since focused on the complex contributions of blood flow on vessel network development and vascular homeostasis. 

Modeling human biliary development and diseases from human pluripotent stem cells 

Scientific Director of the Liver Regenerative Medicine Program
McEwen Centre for Regenerative Medicine, University Health Network CANADA;
Professor (specially appointed), Shinshu University School of Medicine, JAPAN

Dr. Shinichiro Ogawa is a scientific director of the Liver Regenerative Medicine Program in the McEwen Centre for Regenerative Medicine. He received M.D. in 1994 from Tokyo medical university. He then served as a hepato-biliary surgeon over 10 years at Shinshu University in Japan, where the first adult living donor liver transplantation was successfully performed in history. He obtained a Ph.D. from Shinshu University for the study of the generation of hepatocytes from murine embryonic cells. He then started a postdoctoral research at the Gordon Keller lab in McEwen Centre since 2007. His research focuses on the stem cell biology that establishes a method to generate hepatocytes and cholangiocytes (bile duct cells) from human pluripotent stem cells (hPSCs). He leads the Liver Program in the McEwen Centre to produce 3D functional liver tissues from hPSCs for modeling liver diseases in vitro and the transplantation study to treat the animal models with liver diseases. He is also a Professor at the Center for Tissue Transplantation and Regenerative Medicine in Shinshu University. 

Two decades of Alagille syndrome research: Advances and challenges

Evelyn Willing Bromley Professor of Pediatric Pathology
The Children’s Hospital of Philadelphia

Nancy B. Spinner, PhD is the Evelyn Willing Bromley Professor of Pediatric Pathology at The Children’s Hospital of Philadelphia. She received her PhD training at The University of California at Berkeley, and her Fellowship Training in Cytogenetics at The Children’s Hospital of Philadelphia. Her research interests are in the identification of the genetic etiology of Pediatric Disease and the utilization of genome-wide tests for diagnostics. Her laboratory has studied Alagille syndrome since 1992 and her highly collaborative team has made a number of contributions to understanding the genetics of Alagille syndrome. She has also focused on understanding the genetics of Biliary Atresia and the Ring Chromosome 14 and 20 syndromes. She serves on the Scientific Advisory Board of the Alagille Syndrome Alliance, and is on the Editorial Board of Human Mutation, PLoS Genetics and the National Institute on Deafness and Other Communication Disorders Board of Scientific Counselors . She is currently the Chief of the Division of Genomic Diagnostics, which focuses on integrated genetic testing for pediatric disorders. She has received multiple teaching awards at The University of Pennsylvania, and a Faculty Mentoring Award from the Children’s Hospital of Philadelphia. 

Role of notch signaling in biliary repair

Professor of Medicine 
Director, Yale Liver Cancer Program & Deputy Director, Yale Liver Center
Department of Medicine, Yale School of Medicine

Mario Strazzabosco MD, PhD is Professor of Medicine at Yale University, CT. He is Deputy Director of the Yale Liver Center and is Director of the Yale Liver Cancer Program. He graduated from the University of Padova where he obtained the specialty boards in Internal Medicine and in Digestive Diseases. He also otained a PhD degree from the University of Milan and worked as a post-doctoral fellow in dr. Boyer’s lab at Yale. Furthermore Dr. Strazzabosco also attended a number of courses in health care management with focus on total quality management and value based medicine. Dr. Strazzabosco was the founding chief of the GI section at the “Ospedali Riuniti of Bergamo” where he was also Medical Director of Transplantation and then moved back to Yale University (USA), as Professor of Internal Medicine and Gastroenterology, Director of the Transplant Hepatology Unit and Deputy Director of the Yale Liver Center. Dr. Strazzabosco has also served as a Professor of Gastroenterology at the University of Milan-Bicocca in Italy and founding chief of the Section of Digestive Diseases, Chair of the Department of Surgery and Translational Medicine and Vice-president of the School of Medicine. Dr. Strazzabosco is a member of several scientific societies and charity boards. He has served as Associate editor of Hepatology and of Liver International. He serves as a scientific reviewer for several funding bodies in US and Europe and is a regular member of the NIH HPPB study section. Dr. Strazzabosco is the principal investigator in a number of national and international research projects in the field of hepatology, liver transplantation and health care management and directs an NIH-sponsored lab at the Yale University School of Medicine. The scientific activities of Dr. Strazzabosco has resulted in numerous publications in the major international journals. The main current research interests relate to the pathophysiology of biliary tract disease, biology of liver stem cells and liver repair, liver transplantation and liver cancer. He has given more than 200 invited lectures and received numerous awards, including the BBV Foundation Chair, the gold medal of the Friends Association of Organ transplantation. He was also awarded the Master of Art privatim for academic merits from Yale University. He is a Fellow of the American College of Gastroenterology (FACG) and a Fellow of the European Board of Surgery (transplant) (FEBS). 

Engineering microenvironments to study liver differentiation

Assistant Professor 
Department of Bioengineering
University of Illinois at Urbana-Champaign

Gregory H. Underhill is an Assistant Professor of Bioengineering at the University of Illinois at Urbana-Champaign. Dr. Underhill received his PhD from Northwestern University, with his doctoral research focused on the mechanisms controlling the tissue recruitment of T lymphocytes and the functional characteristics of antibody secreting plasma cells. Dr. Underhill completed a postdoctoral fellowship in Dr. Sangeeta Bhatia’s laboratory at MIT, where he worked to develop and apply engineered cell culture platforms towards the study of cell functions. His current research is focused on studying cellular fate decisions, including the tissue development and engineering of the liver. These efforts are at the interface of cell and developmental biology, genomics, biomaterials, and microfabrication. Dr. Underhill’s lab has recently developed a cell microarray platform to enable the systematic analysis of liver progenitor cell fate specification within defined microenvironments, and in particular, facilitate the assessment of interactions between TGF beta, Notch, and other microenvironmental cues including extracellular matrix. These efforts suggest that mechanical signals may also play role in liver progenitor cell function, and that spatial patterns of cell mechanotransduction can cooperate with Notch and other signals to regulate differentiation.