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.
Masaoki Kawasumi, MD, PhD (Medicine/Dermatology)
Our research focuses on UV-induced DNA damage responses and skin cancer development. More recently, we study epigenetic aspect of skin differentiation and skin cancer evolution, investigating what DNA/histone modifications in hair follicle stem cells (the origin of skin cancer) contribute to the development of different subtypes of skin cancer. Our long-term goal is to better understand epigenetic mechanisms in hair follicle stem cells and cancer and use the fundamental knowledge to prevent and inhibit skin diseases including skin cancer.
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.
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.
Stephen Plymate, MD (Medicine/Gerontology and Geriatric Medicine)
Our lab focuses on prostate cancer, specifically we are interested in the targeting of prostate cancer stem cells that lead to tumor regrowth following anti androgen receptor therapy. We are especially interested in the switch between oxidative phosphorylation and glycolysis as an energy source in promoting growth. To this end we have developed specific small molecule inhibitors of glycolysis that are on track for phase 1 clinical trials.
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.
Hannele Ruohola-Baker, PhD (Biochemistry)
The Ruohola-Baker laboratory is dissecting the molecular mechanisms that control stem cell self-renewal and regeneration capacity, both in normal and pathological situations. The laboratory has identified metabolic differences between pluripotent, pre- and post-implantation ESC and is now dissecting how metabolites regulate the stem cell epigenetic state. The laboratory works on three questions: 1) metabolic determinants of stem cells and regeneration 2) stem cell aging and 3) using stem cells to dissect the mechanism of disease states. The laboratory will dissect the etiology of long chain fatty acid induced SIDS, a heart defect that can cause sudden infant death. The laboratory will also study Amelogenesis Imperfect (AI), a defects in stem cells for ameloblasts that normally deposit enamel, the hardest tissue in our body.
Jay Shendure, MD, PhD (Genome Sciences)
The primary mission of our lab is to develop and apply new technologies at the interface of genomics, molecular biology and developmental biology.
Most genetic variants that contribute to the risk or severity of common and rare diseases fall in regions of the human genome that control the expression of genes, rather than in the genes themselves. Although we have learned the hallmark characteristics of such “enhancer” regions, it has been exceedingly difficult to pinpoint which genetic variants within them are disease-contributory and which gene(s) they act through.
We have been working on implementing and advancing stem cell models of development, including gastruloids and embryoid bodies, and implementing multiplex CRISPR-based screens in them in order to identify regulatory elements and variants that may impact development.
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.