Karol Bomsztyk, MD (Medicine/Allergy and Infectious Diseases)
Understanding the processes that signal gene expression is critically important for using stem cells in the treatment of disease. These intracellular processes include many factors that are organized into signaling cascades that regulate genes in the chromatin environment, or the epigenome. To better define these mechanisms our laboratory has been developing advanced epigenetic technologies and computational tools. Our and other member laboratories of the UW Medicine Institute for Stem Cell and Regenerative Medicine are already using these methods to better understand and treat cancer, diabetes, kidney, heart and other diseases where stem cell biology holds great promises.
Christine Disteche, PhD (Pathology)
Research in my lab focuses on the regulation of the mammalian X chromosome.
Zhijun Duan, PhD (Medicine/Hematology)
Our research activities focus on deciphering the structure-function relationship of the genome to understand the molecular mechanisms underlying human development and tumorigenesis. It is increasingly recognized that the genetic materials, i.e., the genomic DNA, in human cells are nonrandomly organized into nested hierarchy in the three-dimensional (3D) space of the nucleus and this spatial organization critically impacts human health and disease, including cancer. Defects in the 3D genome organization have been observed in a wide spectrum of human diseases. Over the past years, we have developed a series of cutting-edge genomic tools for delineating the 3D genome organization globally or locally.
In addition to developing innovative technologies, we are using these tools to investigate how the 3D genome organization goes wrong in blood disorders. Nuclear dysplasia, i.e., abnormal changes in the size and shape of the nucleus, such as hyper-segmented neutrophils, hypolobated neutrophils and acquired Pelger–Huët anomalies (PHAs), is a hallmark for the diagnosis of many hematologic disorders, such as myelodysplastic syndromes (MDS). MDS are a group of clonal disorders of hematopoietic stem and progenitor cells. Characterized by dysplastic hematopoiesis, cytopenia and increased risk of progression to acute myeloid leukemia (AML), MDS remains a poorly treated, life-threatening disease. It remains unclear how the nuclear dysplasia that defines these disorders relates to MDS pathogenesis. To understand how 3D genome disruption may lead to MDS, we are using population-based and single-cell assays to identify abnormal features of the 3D genome and cis-regulatory landscapes in MDS blood cells, with the goal to provide new pathophysiological insights that has the potential to pave the way for developing better MDS diagnostics and therapeutics.
Hao Yuan Kueh, PhD (Bioengineering)
Our lab studies how immune cells make fate decisions, both as they develop from stem and progenitor cells, and as they respond to antigens. We combine live cell imaging, mathematical modeling, as well as modern genetic, biochemical, and high throughput approaches to dissect the molecular circuitry underlying fate control at the single cell level. Our work will lay foundations for engineering immune cells to treat cancer and other life-threatening diseases.
Shin Lin, MD, PhD, MHS (Medicine/Cardiology)
The Lin Lab is interested in understanding the epigenomic changes which occur in cardiovascular disease states. The lab employs the latest in second generation sequencing methods to identify various regulatory elements on a global scale on human samples collected from the operating room. Generated data are subsequently analyzed in the context of other big data from public repositories on a computer cluster. High throughput methods involving stem cell differentiated cardiomyocytes are employed for subsequent in vitro validation. Murine models are also utilized to study key genes within a physiological framework. The research of the lab thus involves procurement of samples in the clinical setting, computational biology, statistics, molecular biology, stem cell culturing, and mouse work. By exploring the epigenomic changes of cardiovascular disease states, the hope is that new avenues for therapies will be discovered.
David L. Mack (Rehabilitation Medicine)
The Mack laboratory combines stem cell and gene therapies to develop new treatments for neuromuscular diseases. Induced pluripotent stem cell technology is used to generate patient-specific stem cells that can undergo directed-differentiation to multiple lineages in culture. Three-dimensional scaffolds are also being employed to further differentiate each cell type into their more mature form. This so called “disease-in-a-dish” approach will enable us to study disease mechanisms, and to create novel drug discovery platforms. Drugs identified in this way are likely to work in the patient since the patient’s own cells were used as the screening tool. Diseases being explored include Duchenne muscular dystrophy, X-linked myotubular myopathy and autistic syndrome disorder.
Dr. Mack is a classically trained geneticist with expertise in developmental and stem cell biology. During his postdoctoral fellowship at the National Cancer Institute, he studied how the stem cell microenvironment controls cell fate during mammary gland development. His recent contributions to the field of regenerative medicine center on the interplay between a cell’s genetic program and it microenvironment during lineage commitment.
Daniel G. Miller, MD, PhD (Pediatrics)
Dr. Miller and members of his research group utilize induced pluripotent stem cells (IPSc) made from the skin cells of individuals with Facioscapulohumeral Muscular Dystrophy (FSHD) to understand the etiology of this debilitating condition. The hypothesis is that FSHD is caused by a defect in muscle development and/or maintenance so studying differences between control and patient embryonic cells as they differentiate to form muscle may reveal key mechanisms of disease pathology. Dr. Miller is also interested in treatment strategies for genetic conditions so members of his research group use vectors based on Adeno-Associated Virus (AAV) to perform gene targeting in primary human cells. This approach is currently being applied to keratinocytes from patients affected with a skin blistering condition called Epidermolysis Bullosa. The molecular consequence of disease-causing mutations can also be studied by creating the same mutations in primary human cells, or correcting mutations in cells from affected patients.
Dr. Miller also sees patients with genetic conditions in the pediatric medical genetics clinic at Children’s Hospital.
Ray Monnat, PhD (Pathology, Genome Sciences)
Our research focuses on human RecQ helicase deficiency syndromes such as Werner syndrome; high resolution analyses of DNA replication dynamics; and the engineering of homing endonucleases for targeted gene modification or repair in human and other animal cells.
Thalia Papayannopoulou, PhD (Medicine/Hematology)
Dr. Thalia Papayannopoulou’s research program aims to understand the mechanisms whereby hematopoietic stem cells home to bone marrow following transplantation, and how they traffic between the marrow and the blood stream under normal and perturbed hematopoiesis. A particular focus is on the characterization of the hematopoietic stem cell niche. In addition, Papayannopoulou lab studies erythroid cell development during the embryonic, fetal and adult stages of development.
David W. Raible, PhD (Biological Structure)
We are interested in the development of the peripheral nervous system using zebrafish as a model. Current research focuses on two areas: sensory neurons derived from neural crest and the mechanosensory lateral line system.
Yuliang Wang, PhD (Computer Science & Engineering)
Pluripotent stem cell differentiation and tissue development are often accompanied by significant metabolic shifts. It is increasingly recognized that metabolic states are not merely the byproduct of cellular signaling, but can actively influence cell fate decision. In particular, cellular epigenetic states (histone and DNA methylation, histone acetylation) and intermediary metabolism are interconnected by key metabolites such as S-Adenosyl methionine, α-ketoglutarate, acetyl-CoA. My research aims to integrate transcriptomics, epigenetics and network modeling to understand the how metabolic network state influences stem cell differentiation and tissue development via its effects on epigenetic modifications. This research can lead to efficient metabolic approaches (changing medium culture, inhibiting or activating a metabolic enzyme) to manipulate cell fates.
Thomas N. Wight, PhD (Benaroya Research Institute)
This investigator leads a research program focused on the role that the extracellular matrix molecules, proteoglycans and hyaluronan, play in regulating vascular cell type and the regulation of extracellular matrix assembly. These pathways are fundamental to understanding the growth of new blood vessels in different tissues of the body, and have potential for direct tissue regeneration applications through the use of proteoglycan genes to bioengineer vascular tissue.