Research into the biology of stem cells with a particular focus on their use in regenerative medicine applications.
Labs In This Area
Mechanisms of prostate cancer initiation, progression and recurrence, and strategies to therapeutically target these processes
Our laboratory focuses on understanding the molecular mechanisms that drive prostate cancer initiation, progression and recurrence with the ultimate goal of developing therapeutic strategies that target these processes. Our approach includes the genomic analysis of human tumors, cell culture studies and the use of genetically engineered mouse models. We have a strong interest in genomics and gene regulation, oncogenic kinases as potential molecular therapeutic targets, and the use of in vivo lineage tracing to define the fates of specific cell populations in tumorigenesis.
Specific projects include:
The role of the oncogenic serine/threonine kinase PIM1 in prostate cancer - PIM1 is coexpressed with c-MYC and dramatically enhances c-MYC-driven prostate tumorigenesis in a kinase-dependent manner. Notably, PIM1 is induced in tumors by hypoxia, radiation and treatment with docetaxel, a common but largely ineffective option for patients with advanced castration-resistant prostate cancer. PIM1 induction by hypoxia/radiation/docetaxel promotes prostate cancer cell survival and therapeutic resistance. Therefore, PIM1 may represent a valuable therapeutic target in prostate cancer. We are using new mouse models of prostate cancer for testing the efficacy of novel PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance. We have also identified novel candidate PIM1-interacting proteins in prostate epithelial cells. Among the proteins identified are a MYC transcriptional cofactor and a prostate stem cell marker/regulator. We are investigating how PIM1 promotes prostate tumorigenesis by phosphorylating these substrates involved in regulating MYC transcriptional activity and stem cell function.
Cellular and molecular determinants of prostate cancer recurrence - A major clinical problem in prostate cancer is that of tumor recurrence following initial apparently successful therapy. Recurrent tumors may arise from a small number of "cancer stem-like cells" that survive the initial therapeutic intervention and have the capacity to regenerate the tumor. We are using lineage tracing to examine the competence of specific prostate epithelial cell types to regenerate tumors following therapy in mice.
Targeting lethal prostate cancer – We are using our mouse model of lethal prostate cancer based on alterations in Myc, Pten and Tp53 to develop new targeted therapies. One current project involves the targeting of EphB4 receptor tyrosine kinase using an antagonist as a therapeutic strategy.
For more information, see Dr. Abdulkadir's faculty profile.
See Dr. Abdulkadir's publications in PubMed.
Meejeon Roh—Research Assistant Professor
Yvonne Feeney—Lab Manager
Tanushri Sengupta—Research Associate
Kenji Unno—Research Associate
Rose Njoroge—Graduate Student
Rajita Vatapalli—Graduate Student
Lab Telephone: 312-503-5031
Studying the role of the glucocorticoid receptor in carcinogenesis and stem cell maintenance. Involved in development GR-targeted therapies in skin.
The current projects in Dr. Budunova’s lab are centered on the role of the glucocorticoid receptor (GR) as a tumor suppressor gene in skin. We showed that skin-specific GR transgenic animals are resistant to skin carcinogenesis, and GR KO animals are more sensitive to skin tumor development. We are also interested in the role of GR in the maintenance of skin stem cells (SC). We found that GR/glucocorticoids inhibit the expression of numerous SC markers in skin including CD34- a marker of hair follicular epithelial SC, and reduce the proliferative potential of skin SCs.
The glucocorticoids remain among the most effective and frequently used anti-inflammatory drugs in dermatology. Unfortunately, patients chronically treated with topical glucocorticoids, develop side effects including cutaneous atrophy. GR controls gene expression via (i) transactivation that requires GR dimerization and binding as homo-dimer to gene promoters, and (ii) transrepression that is chiefly mediated via negative interaction between GR and other transcription factors including pro-inflammatory factor NF-kB. In general, GR transrepression is the leading mechanism of glucocorticoid anti-inflammatory effects, while many adverse effects of glucocorticoids are driven by GR transactivation.
Our laboratory has been involved in delineation of mechanisms underlying side effects of glucocorticoids in skin. Using GRdim knockin mice characterized by impaired GR dimerization and activation, we found that GR transactivation plays an important role in skin atrophy. These data suggested that non-steroidal selective GR activators (SEGRA) that do not support GR dimerization, could preserve therapeutic potential of classical glucocorticoids but have reduced adverse effects in skin. We are testing effects of the novel SEGRA called Compound A– a synthetic analog of natural aziridine precursor from African bush Salsola Botch in skin. We have also established anti-cancer GR-dependent activity of Compound A in epithelial and lymphoma cells.
Using knockout mice for the major GR target genes including Fkbp5 (GR chaperone) and DDIT4/REDD1 (one of the major negative regulators of mTORC), we discovered that blockage of Fkbp5 and REDD1 significantly changes GR function, and greatly protects skin against glucocorticoid-induced atrophy. This suggests a novel GR-targeted anti-inflammatory therapy where glucocorticoids are combined with inhibitors of GR target genes.
For more information, please see Dr. Budunova’s faculty profile.
See Dr. Budunova's publications in PubMed.
Contact Budunova Lab
Contact the Budunova Lab at 312-503-4669 or visit in the Montgomery Ward Building, 303 E. Chicago Avenue, Ward 9-015, Chicago, IL 60611
Investigating the application of human induced pluripotent stem cells to study the pharmacogenomics of chemotherapy off-target toxicity and efficacy
The Burridge lab studies the role of the genome in influencing drug responses, known as pharmacogenomics or personalized medicine. Our major model is human induced pluripotent stem cells (hiPSC), generated from patient's blood or skin. We use a combination of next generation sequencing, automation and robotics, high-throughput drug screening, high-content imaging, tissue engineering, electrophysiological and physiological testing to better understand the mechanisms of drug response and action.
Our major effort has been related to patient-specific responses to chemotherapy agents. We ask the question what is the genetic reason why some patients have a minimal side-effects to their cancer treatment, whilst others have encounter highly detrimental side-effects. These side-effects can include cardiomyopathy (heart failure or arrhythmias), peripheral neuropathy, or hepatotoxicity (liver failure). It is our aim to add to risk-based screening by functionally validating genetic changes that predispose a patient to a specific drug response.
- Human induced pluripotent stem cells predict breast cancer patients’ predilection to doxorubicin-induced cardiotoxicity
- Chemically defined generation of human cardiomyocytes
- Modeling the role of the genome in doxorubicin-induced cardiotoxicity using hiPSC
- Investigating the pharmacogenomics of tyrosine kinase inhibitor cardiotoxicity
- hiPSC reprogramming, culture, and differentiation techniques
- High-throughput and high-content methodologies in hiPSC-based screening
See Dr. Burridge's publications on PubMed.
Contact Dr. Burridge at 312-503-4895.
Cancer stem cell biology, cellular signaling and therapy responses in human brain tumors, in particular, glioblastoma (GBM)
Integrated genomic analysis by TCGA revealed tat GBMs can be classified into four clinically relevant subtypes, proneural (PN), neural, mesenchymal (Mes) and classical GBMs with each characterized by distinct gene expression signatures and genetic alterations. We reported that PN and Mes glioma stem cells (GSCs) subtypes also have distinct dysregulated signaling pathways. Our current research focuses on novel mechanisms/cellular signaling of GSC biology, tumorigenesis, progression, invasion/metastasis, angiogenesis and therapy responses of GSCs and GBMs.
1. MicroRNAs (miRs) and non-coding RNAs in GSCs and GBMs – miRs and other small non-coding RNAs act as transcription repressors or inducers of gene expression or functional modulators in all multicellular organisms. Dysregulated miRs/noncoding RNAs plays critical roles in cancer initiation, progression and responses to therapy. We study the mechanisms by which deregulated expression of miRs influence GBM malignant phenotypes through interaction with signaling pathways, that in turn, influence proneural (PN)- and mesenchymal (Mes)-associated gene expression in GSCs and GBM phenotypes. We study the molecular consequences and explore clinical applications of modulating miRs and signaling pathways in GBMs. We are establishing profiles of non-coding RNAs in these GSCs and study mechanisms and biological influences of these non-coding RNAs in regulating GSC biology and GBM phenotypes. In addition, we explore novel therapeutic approaches of delivery of tumor suppressive miRs into GSC brain xenografts in animals.
2. Autophagy in GBMs. (Macro)autophagy is an evolutionally conserved dynamic process whereby cells catabolize damaged proteins and organelles in a lysosome-dependent manner. Autophagy principally serves as an adaptive role to protect cells and tissues, including those associated with cancer. Autophagy in response to multiple stresses including therapeutic treatments such as radiation and chemotherapies provides a mechanism for tumor cell to survive and acquire resistance to therapies. Tumors can use autophagy to support and sustain their proliferation, survival, metabolism, invasiveness, metastasis, and resistance to therapy. We study mechanisms by which phosphorylation, acetylation and ubiquitination of autophagy proteins regulate GSC and GBM phenotypes and autophagic response, which, in turn contributes to tumor cell survival, growth and resistance to therapy. We investigate whether disruption of these post-translational processes on autophagy proteins inhibits autophagy and enhances the efficacy of combination therapies for GBMs. We examine whether cross-talks between miRs, autophagy and oncogenic signaling pathways regulate GSC stemness and phenotypes.
3. Heterogeneity, epigenetic regulation, DNA damage and metabolic pathways in GSCs and GBMs. Intratumoral heterogeneity is a characteristic of GBMs and most of cancers. Phenotypic and functional heterogeneity arise among GBM cells within the same tumor as a consequence of genetic change, environmental differences and reversible changes in cell properties. Subtype mosaicism within the same tumor and spontaneous conversion of human PN to Mes tumors have been observed in clinical GBMs. We explore an emerging epigenetic marker with distinct functions such as DNA methylation together with genetic mapping of these markers to assess their contributions to GBM heterogeneity. In addition, compared with PN GSCs, DNA damage and glycolytic pathways are aberrant active in Mes GSCs. We investigate the mechanisms by which these pathways regulate GSC and GBM phenotypes and responses to therapies.
4. Oncogenic receptor tyrosine kinase (RTKs) signaling, small Rho GTPase regulators in GBM and GSCs: Small Rho GTPases such as Rac1 and Cdc42 modulate cancer cell migration, invasion, growth and survival. Recently, we described mechanisms by which EGFR and its mutant EGFRvIII, and PDGFR alpha promote glioma growth and invasion by distinct mechanisms involving phosphorylation of Dock180, a Rac-specific guanidine nucleotide exchange factor (GEF) and DCBLD2, an orphan membrane receptor. We are currently investigating involvement of other modulators/GEFs and other Rho GTPases in modulating GSC and GBM phenotypes and responses to therapy.
View Dr. Cheng's complete list of publications in PubMed.
Shi-Yuan Cheng, PhD at 312-503-5314
Visit us on campus in the Lurie Building, Room 6-119, 303 E Superior Street, Chicago, Illinois 60611.
Research Associate Professor
Namratha Sastry (rotating)
The Crispino laboratory studies the mechanisms of normal and malignant blood cell growth.
Research in the Crispino laboratory is focused on investigating the regulatory mechanisms governing normal and malignant blood cell development, with an emphasis on understanding the growth of erythroid cells (red blood cells) and megakaryocytes (platelet-producing cells). Major areas of focus include: 1) Understanding the link between Down syndrome and leukemia. We are investigating how mutations in GATA1, a key transcription factor that regulates megakaryocyte growth contribute to leukemia. We are also studying the mechanisms by which trisomy 21 promotes the development of leukemia with a long-term goal of unraveling the mystery of why children with DS are predisposed to leukemia. Our current efforts are focused on characterizing the contributions of two chromosome 21 genes: DYRK1A, a kinase, and ERG, a transcription factor. 2) Development of novel therapeutics for human megakaryocytic malignancies. In collaboration with the Broad Institute, we identified several small molecules that induce proliferation arrest, polyploidization and maturation of malignant megakaryocytes. By a three-pronged target identification approach, we discovered that a key target of these small molecules is Aurora A Kinase. We are currently investigating the utility of AURKA inhibitors as potential new, targeted therapies for acute megakaryocytic leukemia. In addition, we have completed extensive pre-clinical studies to support the testing of AURKA inhibitors in a related blood disease named primary myelofibrosis, a subtype of the MPNs. 3) Investigating the mechanisms of red blood cell development. We are currently studying two aspects of red blood cell development. First, based on our previous discovery that the coalescence of cytoplasmic vesicles is required for enucleation of erythroblasts, we are probing the requirements for specific motor proteins in enucleation and identifying small molecules that enhance enucleation in culture. This research will aid in the development of new strategies to generate red blood cells for transfusion in vitro from stem cells. Second, in line with our expertise and significant interest in GATA1 biology, we are studying the effects of GATA1 mutations on erythropoiesis. We are using state of the art approaches to identify essential, direct GATA1 target genes whose expression depends on the presence of the full-length wild-type protein. This research is relevant to rare red blood cell disorders such as Diamond Blackfan Anemia. Overall, the lab seeks to make seminal basic science discoveries while simultaneously translating these discoveries in ways that will benefit patients with hematologic malignancies.
View lab publications via PubMed.
For more information, visit the faculty profile page of John Crispino, PhD.
Contact Dr. Crispino at 312-503-1504 or the Crispino Lab at 312-503-1433.
Gina Kirsammer, PhD
Research Assistant Professor
Paul Lee, MD, PhD
Pediatric Hematology/Oncology Fellow
Monika Stankiewicz, PhD
Praveen Suraneni, PhD
Benjamin Thompson, MD/PhD
Qiang (Jeremy) Wen, MD/PhD
Research Assistant Professor
Qiong Yang, MD/PhD
Focusing on the biology of neural stem cells and growth factors and their potential for regenerating the damaged or diseased nervous system.
The Kessler laboratory focuses on the biology of neural stem cells and growth factors and their potential for regenerating the damaged or diseased nervous system. A major interest of the laboratory has been the role of bone morphogenetic protein (BMP) signaling in both neurogenesis and gliogenesis and in regulating cell numbers in the developing nervous system. Both multipotent neural stem cells and pluripotent embryonic stem cells are studied in the laboratory, and recent efforts have emphasized studies of human embryonic stem cells (hESC) and human induced pluripotent stem cells (hIPSC). The Kessler lab oversees the Northwestern University ESC and IPSC core, and multiple collaborators use the facility. In addition to the studies of the basic biology of stem cells, the laboratory seeks to develop techniques for promoting neural repair in animal models of spinal cord injury and stroke. In particular the lab is examining how stem cells and self-assembling peptide amphiphiles can be used together to accomplish neural repair. The lab is also using hIPSCs to model Alzheimer’s disease and other disorders.
For more information see the faculty profile of John A Kessler, MD.
View Dr. Kessler's full list of publications in PubMed.
Roles of chondroitin sulfates and genes/proteins in the chondroitin sulfate biosynthesis pathway in development and disease
My laboratory is interested in the functional roles of chondroitin sulfates and chondroitin sulfotransferase genes in mammalian development, disease, and cellular signaling pathways. Specifically, we have been investigating the roles of the sulfotransferase C4ST-1/CHST11 and its chondroitin sulfate product CS-E in the contexts of breast cancer progression, the pediatric disease Costello syndrome, cardiovascular disease, developmental processes including embryonic stem cell differentiation and cell lineage determination, and in the control of Wnt/beta-catenin and HRAS signaling. Our long-term goal is the development of carbohydrate-based pharmacological interventions for the treatment of human diseases, including cancer and cardiovascular disease.
For more information, view the faculty profile of Michael Klüppel, PhD.
See Dr. Klüppel's publications in PubMed.
Michael Klüppel, Ph.D.
Catherine M. Willis, Ph.D.
Robert Prinz, M.D.
Looking to describe and probe the role of nuclear organization in stem cell maintenance and differentiation
Our work looks to describe and probe the role of nuclear organization in stem cell maintenance and differentiation. We aim to characterize the mechanistic role transcription plays in organizing the nucleus during the renewal and commitment of stem cells and determine the ability of the nucleoskeleton to dynamically integrate cellular signals that yield these two fates. We suggest that these studies will be relevant to our understanding of the role stem cells play in aging and disease states such as cancer.
See Dr. Kosak's publications on PubMed.
Contact Dr. Kosak at 312-503-9582.
Understanding the mechanisms of neuronal dysfunction in neurodegenerative disorders that affect children and adults.
The overarching goal of my laboratory is to study rare diseases such Huntington’s and genetic forms of Parkinson’s disease, as a window to understanding neurodegeneration across the lifespan. More recently, we have focused on rare lysosomal diseases such as Gaucher’s in order to identify specific targets and mechanisms that contribute to neurodegeneration in Parkinson’s and related synucleinopathies. It is expected that such defined targets will facilitate mechanism-based development of targeted therapies for children with neuronopathis Gaucher’s disease as well as adult-onset synucleinopathies such as Parkinson’s disease. To validate and study these targets and novel therapies in human neurons, we have utilized induced pluripotent stem cells (iPS) generated by reprogramming of patient-specific skin fibroblasts. These iPS cells are differentiated into specific neuronal subtypes in order to characterize the contribution of genetic, epigenetic and environmental factors to disease mechanisms and to test novel therapeutic approaches.
View Dr. Krainc's full list of publications in PubMed.
Dimitri Krainc, MD, PhD
Ward Professor and Chairman
The Kume Lab’s research interests focus on cardiovascular development, cardiovascular stem/progenitor cells, and angiogenesis.
Cardiovascular development is at the center of all the work that goes on in the Kume lab. The cardiovascular system is the first functional unit to form during embryonic development and is essential for the growth and nurturing of other developing organs. Failure to form the cardiovascular system often leads to embryonic lethality, and inherited disorders of the cardiovascular system are quite common in humans. The causes and underlying developmental mechanisms of these disorders, however, are poorly understood. A particular emphasis in our laboratory has recently been the study of cardiovascular signaling pathways and transcriptional regulation in physiological and pathological settings using mice as animal models, as well as embryonic stem (ES) cells as an in vitro differentiation system. The ultimate goal of our research is to provide new insights into the mechanisms that lead to the development of therapeutic strategies designed to treat clinically relevant conditions of pathological neovascularization.
View Dr. Kume's publications on PubMed.
For more information, visit the faculty profile for Tsutomu Kume, PhD.
Contact Dr. Kume at 312-503-0623 or the Kume Lab at 312-503-3008.
Regulation of Motor Neuron and Dopaminergic Neuron Function in Development and Disease
Postdoctoral fellow jobs and graduate student rotation projects are available.
Research DescriptionSpinal Motor Neurons and Spinal Muscular Atrophy (SMA)
SMA is characterized by the selective degeneration of spinal motor neurons. As the leading genetic cause of infant mortality, SMA affects one in every eight thousand live births. Our group is interested in studying mechanism regulating motor neuron development and function, as well as why motor neurons specifically degenerate in SMA. To address these questions, we use a combination of genetic, biochemical and cell biological approaches, and utilize genetically modified mice, induced pluripotent stem (iPS) cells reprogrammed from fibroblasts, and zebrafish as model systems. We focus on the regulation of mitochondrial functions in SMA pathogenesis. Based on our findings, we hope to develop new therapeutic strategies for treating SMA.
Dopaminergic Neurons and Parkinson's Disease
Dopaminergic neurons located in the ventral midbrain control movement, emotional behavior and reward mechanisms. Dysfunction of these neurons is implicated in Parkinson’s disease, drug addiction, depression and schizophrenia. Our group is interested in the genetic and epigenetic mechanisms regulating dopaminergic neuron functions in disease and aging conditions. We are particularly interested in how aging and mitochondrial oxidative stress contribute to dopaminergic neuron degeneration in Parkinson's disease through transcriptional and epigenetic regulations. We use mouse models, cultured neurons and iPS cells for these studies.
View Dr. Ma's publications at PubMed
Nimrod Miller, PhD, Postdoctoral Fellow
Han Shi, Graduate Student
Brittany Edens, Graduate Student
Kevin Park, Graduate Student
Monica Yang, Undergraduate Student
Aaron Zelikovich, Undergraduate Student
Epigenetics of Stem Cells and the Stem Cell Niche
My lab focuses on how genetic and epigenetic modulators promote the development and maintenance of adult stem cells.
Microenvironments, or niches, support the maintenance of stem cells and facilitate the development of tumors through largely unknown mechanisms. Cell-autonomous genetic pathways and epigenetic networks have emerged as important determinants for the self-renewal and differentiation of stem cells in embryonic, juvenile, and adult tissues. The importance of non-cell autonomous genetic and epigenetic factors is less well established. Our goal is to identify and characterize the genetic and epigenetic mechanisms utilized by both stem cells and their surrounding niche in supporting the stem cell program. For these studies, the developing mouse testis is used to examine interactions between male germline stem cells (GSCs) and their somatic niche.
Within the testis, differentiated germ cells are continually replenished by self-renewing GSCs to ensure the continuation of spermatogenesis throughout the lifetime of the male. GSCs are adult stem cells that develop after birth but which derive from embryonic primordial germ cells (PGCs). Under abnormal conditions, PGCs are thought to become pluripotent in vivo, develop into carcinoma in situ, and form post-pubertal testicular germ cell tumors, the most common cancer in men aged 15-40. When GSC differentiation occurs at the expense of self-renewal, depletion of germ cells and infertility can result.
Several candidate factors influencing GSC self-renewal and differentiation are being studied: chromatin remodeling gene Sin3a, Polycomb group member Ezh2, and a chemokine ligand and its receptor, Cxcl12 and Cxcr4. Current research is examining the role of Sin3a in somatic Sertoli cells, which support GSCs and nurture all differentiating germ cells. Analysis of Ezh2 in GSCs as well as in testicular germ cell tumors is being conducted to determine whether an altered “Polycomb repression signature” promotes germ cell tumorigenesis. Characterization of Cxcl12, which is expressed in Sertoli cells, and Cxcr4, expressed in germ cells, is being performed to determine whether this chemokine signaling pathway is required to maintain GSCs in their niche and whether this mechanism involves non-coding microRNAs.
To achieve these aims, distinct testicular cell populations are separated by fluorescence- and magnetic-activated cell sorting and analyzed by transcriptional profiling. Potential SIN3A and EZH2 complex-bound target genes are identified by chromatin immunoprecipitation. Loss-of-function effects are examined by one of two methods: generation of conditional knockout mice or RNAi knockdown and transplantation of cultured GSCs into recipient testes. Future studies are aimed at understanding how the niche maintains stem cells and ensures proper organogenesis, with the possibility of tissue regeneration and cancer prevention as therapeutic applications.
For more information visit Dr. Payne's faculty profile page
View Dr. Payne's publications at PubMed
Development and regenerative repair of vertebrate limbs and hearts
The development of organs during embryogenesis and their repair during adulthood are biological problems of very practical importance for regenerative medicine.
Using both newt and zebrafish model organisms that naturally rebuild lost structures as adults, we identified evolutionarily conserved gene activities indicative of a molecular signature of regeneration. Particularly, we found the dynamic remodeling of the extracellular matrix (ECM) to be key in instructing cell behaviors that are critical for initiating and maintaining regenerative processes. These findings point to new opportunities for the enhancement of regenerative wound healing in mammals through the manipulation of the local extracellular environment.
As a new research direction, we are studying an unexpected hyperactive blood clotting phenotype in mice deficient for the actin-associated protein Pdlim7. The Pdlim7 knockout mouse provides strong translational opportunities as a novel model to better understand the causes and possible treatments of hypercoagulopathies.
View all publications on PubMed
Phone Dr. Simon at 773-755-6391 or the Simon Lab at 773-755-6372.
Cell and molecular biology of herpesvirus invasion of the nervous system
We investigate the relationship between infection of the nervous system by herpesviruses and disease outcome. Some of the most traumatic diseases – including polio, rabies and encephalitis – result from infections of the nervous system. In contrast, herpesviruses are highly proficient at infecting the nervous system, yet normally do not cause neurological disease. This is achieved in part by self-imposed restrictions encoded within the viruses that limit viral reproduction and prevent dissemination into the brain. For the individual, this results in a relatively benign infection, yet the virus becomes a life-long occupant of the nervous system that will periodically reemerge at body surfaces to infect others. Unfortunately, this infectious cycle can go awry resulting in several forms of severe disease (i.e. keratitis and encephalitis).
We have pioneered methods to genetically manipulate herpesviruses and visualize individual viruses in living neurons. Using these methods, we are studying the mechanisms by which the virus achieves its stringently controlled infectious cycle. Current genetic manipulations are based on a full-length infectious clone of the herpesvirus genome. The clone was made as a bacterial artificial chromosome (BAC) in E. coli. Transfection of purified E. coli BAC plasmid into permissive eukaryotic cells is sufficient to initiate viral infection, allowing for immediate examination of viral mutant phenotypes in a variety of biological assays. For example, by fusing the green fluorescent protein (GFP) to a structural component of the viral capsid, individual viral particles can be tracked within the axons of living neurons during both entry and egress phases of the infectious cycle. Studies in culture can be complemented by examining the pathogenesis of mutant viruses in rodent models of infection.
Using these methods, we have discovered key aspects of cellular infection, viral assembly and intracellular transport. Looking forward, we are continuing to pursue our multidisplinary approach of combining neuroscience, cell biology, bacterial genetics and virology to better understand these important pathogens.
For lab information and more, see Dr. Smith's faculty profile.
See Dr. Smith's publications on PubMed.
Contact Dr. Smith at 312-503-3745 or the lab at 312-503-3744.
Role of homeodomain-containing transcription factors in pancreas and liver organogenesis
My lab investigates mechanisms that establish the complex architecture of 2 vital mammalian organs, the pancreas and liver. Our past studies produced some unique mouse models that helped us begin dissecting the role of homeodomain-containing transcription factors in pancreas and liver organogenesis. Also, these mouse models helped us identify potential new regulators of pancreas and liver cell fate and morphogenesis.
In addition to using mouse models, our current studies incorporate other methods to better address specific questions related to pancreas and liver formation. For instance, we grow ex-vivo explants of mouse embryonic tissues to study pancreas branching morphogenesis or hepatoblast delamination in a dish. We also use in silico and bioinformatics tools to uncover molecular pathways and transcriptional networks regulating pancreas and liver cell specification and differentiation. More recently, we began using protocols of ESCs and iPSCs differentiation to interrogate the function of our genes of interest in early endoderm development or hepatopancreas cell fate specification. Ultimately, my lab will use the knowledge gained from our mouse investigations to address mechanisms of early human pancreas and liver development in organoid and iPS/ESC cultures.
Our studies will generate novel mechanistic information on how specific transcription factors regulate progenitor specification, morphogenesis and cellular plasticity in the murine pancreas, and how altered homeobox gene activity contributes to pancreatic and liver diseases. I also predict that novel key regulators of early hepatic morphogenesis, hepatocyte cell fate, and liver zonation will be identified.
View Dr. Sosa-Pineda's publications at PubMed
Organ and tissue engineering, 3D scaffold systems, induced pluripotent stem cells, stem and progenitor cell differentiation in 3D matrices, regenerative medicine applications
The major area of interest in my laboratory is advancing the state of art in organ regeneration and tissue engineering to develop methods to grow livers and kidneys as a cutting-edge solution to the organ shortage dilemma. Nationally, over 120,000 patients are waiting for solid organ transplantation, yet the number of transplants performed annually falls short of this need by 75%. In the absence of suitable donors for transplantation, organ failure leads to associated health problems, increased health care expenditures and death. Organ shortage is a national issue with local impact. In 2010 there were just over 1050 solitary kidney, liver, or heart transplants performed in Illinois yet 311 patients died in the state alone, and more than 6650 nation-wide, waiting for an organ.
Our research proposes a multidisciplinary solution to organ shortage by utilizing a tissue engineering approach to rehabilitate the extracellular matrix of organs that are not initially suitable for transplantation. Just-in-time organs, reconstituted with recipient derived progenitor cells, would abrogate the need for long waitlist times and associated waitlist mortality, reduce the reliance on organs from living donors, and obviate the need for immunosuppression. Conceptually, these organs would be prepared from a donor matrix using a recipients own cells at the first signs of organ dysfunction. The re-engineered organ would then be ready for implantation when progressive organ failure indicates the need for transplantation.
The traditional paradigm in tissue engineering has been to grow cells on synthetic, polymer scaffolds to recreate the organ or tissue of interest. The limitation of this approach is the scale-up. Beyond a critical distance, diffusion of nutrients and oxygen is not sufficient to support cellular life, and a vascular system must be incorporated into the tissue to supply nutrients. It has been technically difficult to design a synthetic micro-vasculature resembling small, terminal capillaries and to combine these structures with functional cells. Our approach challenges this paradigm by using the natural extracellular matrix as a scaffold to support the growth of new cells capable of repopulating the three-dimensional matrix. We have established protocols to remove parenchyma cells from livers and kidneys with a high efficiency of cellular removal and adequate retention of extracellular matrix molecules. We have further repopulated the vasculature of these matrix structures with endothelial cells derived from induced pluripotent stem cell technology. Together, we have partnered with the McCormick School of Engineering at Northwestern University and other leading academic and industrial centers to advance this fast moving field and address the problem of organ shortage.
View publications by Jason Wertheim at PubMed
Lab Phone 312-695-0257