Genetics, Cell Biology & Anatomy

Shannon Buckley, PhD
Assistant Professor
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Adult and pluripotent stem cell research not only has potential for the future of regenerative medicine, but also holds promise to elucidate pathways altered in malignant transformation due to parallels between stem cells and cancer. The goal of the lab is to utilize genomic and proteomic approaches to identify key ubiquitin ligases and their substrates that regulate mechanisms of pluripotency, self-renewal, differentiation, and hematopoietic malignant transformation. Currently we are focusing on two ubiquitin E3 ligases. First, is the ubiquitin E3 ligase FBXO9, which is dynamically regulated during cellular reprogramming, and silencing facilitates the induction of pluripotency. In addition, FBXO9 interacts with a number of novel proteins associated with pluripotency and early embryonic development. These findings lead to the working hypothesis that the ubiquitin E3 ligase FBX09 can control pluripotency and stem cell function. Second, is a HECT domain E3 ligase, UBR5, we found to regulate cell fate decisions in embryonic stem cells. Interestingly, UBR5 is disrupted in a number of cancers and more recently was found to be mutated in ~18% of patients with mantle cell lymphoma.  Frame shift mutations are found within the HECT domain of UBR5, which can accept and transfer ubiquitin molecules to the substrate, leading to a premature stop codon prior to the cysteine residue associated with ubiquitin transfer. Although Ubr5 is expressed in hematopoietic cell lineages, the role in hematopoietic development and maintenance is unknown. Determining the role of UBR5 and interacting partners in hematopoiesis will provide insights into mantle cell lymphoma transformation and progression as well as potentially identify therapeutic targets. The dynamic reversibility of the ubiquitin modification (by kinases, phosphatases, E3 ligases and de-ubiquitinases) and recent success of a UPS inhibitor (Velcade) for the treatment of multiple myeloma and mantle cell lymphoma proves the translational importance of the UPS system. This suggests that targeting of specific elements of the UPS could lead to future breakthroughs in both basic research and cancer therapy by leading to more efficient generation of induced pluripotent stem cells, promoting lineage differentiation for cell therapy, and provide potential targets for drug discovery.

For more information on Dr. Buckley: Website

Andrew T. Dudley, PhD
Associate Professor
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Research in the Dudley Laboratory is focused on understanding the mechanisms of cartilage degeneration and on the development of tissue engineering and regenerative medicine approaches to treat cartilage and bone defects. To accomplish these goals, we study prenatal and postnatal development of model organisms to elucidate the molecular basis of tissue formation and then we apply this knowledge to the development of three-dimensional in vitro tissue systems to generate models to advance studies of disease mechanisms and cartilage regeneration. Current projects include studies of growth plate architecture and biomechanics, the origin of osteoarthritis, and the generation of full-thickness articular cartilage for transplantation.

For more information on Dr. Dudley: Website

Gargi Ghosal, PhD
Assistant Professor
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Genome Instability: Replication stress response in cancer and premature aging disorders.
The research focus of the laboratory is to examine the molecular basis of replication stress response in cancer and age-related disorders. Replication stress results due to stalling of the DNA replication machinery when it encounters, secondary DNA structures, DNA damage or due to factors that alter the levels of dNTP pool, proteins involved in DNA synthesis, hyper-DNA replication caused by the activation of origins and by oncogene over-expression. Stalled forks lead to fork collapse resulting in cell death or chromosomal abnormalities leading to cancer, genetic disorders, aging and diseases with cancer predisposition such as Werner syndrome, Bloom syndrome, Fanconi anemia, to name a few. The laboratory is interested in understanding the molecular mechanism of replication stress response upon DNA damage and oncogene-induced replication stress with the focus on:

  1. A) Roles of Spartan (SPRTN) and SPRTN mediated DNA-protein cross-link repair in early-onset hepatocellular carcinoma and premature aging. We identified SPRTN as a key regulator of translesion DNA synthesis (TLS). Mutations in SPRTN gene cause RJALS syndrome characterized by early-onset hepatocellular carcinoma, genome instability and progeroid features. SPRTN protein is a protease that is involved in the repair of DNA-protein crosslinks in the genome. We are interested in elucidating the molecular and physiological functions of SPRTN and SPRTN mediated TLS and DPC repair in replication stress, genome instability and cancer.
  2. B) Oncogene-induced replication stress response in Ewing Sarcoma. EWS-FLI1 gene fusion causes Ewing sarcoma, second most common primary bone cancer affecting children. Deregulated expression of EWS-FLI1 transcriptional targets have shown to drive oncogenesis, but do not fully explain the disease phenotype. Additional roles of EWS-FLI1 in DDR and cell-cycle checkpoint is only beginning to unravel. We are investigating the roles of EWS and FLI1 in DDR upon replication stress and how these functions are altered by the expression of the pathological EWS-FLI fusion protein in Ewing sarcoma. The potential effects on sarcoma oncogenesis and drug resistance will be studied.
  3. C) Replication stress response signaling and DNA repair. Identifying key enzymes and pathways that stabilize and repair stalled forks; study the regulatory mechanisms of replication stress response signaling and repair processes and; the cross-talk of cell-cycle checkpoint and DNA repair pathways that function to remove DNA lesions.

While replication stress can lead to development of cancer, on the other hand, inducing replication stress is the mode of action of most chemotherapeutic drugs used to kill cancer cells. These studies will help understand the basic science underlying replication stress response, identify new targets and bio-markers for cancer therapy and facilitate the development of strategies to overcome drug resistance and improve cancer therapy.

For more information on Dr. Ghosal: Website

Karen A. Gould, PhD
Associate Professor
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Research Interests:  The research in my lab is focused on understanding how genes and hormones impact our risk of developing certain diseases. One project seeks to understand how the hormone estrogen impacts the risk of developing lupus, an autoimmune disease that is ~10 times more common in women than men. We also study how the action of genetic factors that impact lupus risk are influenced by estrogens. A second project focuses on determining the role of genetic factors and estrogens in the risk of colon cancer, which is more common in men than women. This research will not only enhance our understanding of how genes and hormones impact disease risk, but also has the potential to assist in the development of more effective prevention and treatment of these diseases. Toward this goal, my lab is currently investigating the use of targeted drug delivery systems to deliver hormone modulating drugs to treat these diseases.

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Chittibabu (Babu) Guda, PhD
Professor
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Research Interests: My laboratory nurtures a wide variety of research areas related to bioinformatics. Research topics can be broadly grouped under novel method development, data mining and knowledge discovery, and the application of machine learning tools to solve biological problems. In addition, we have been developing and supporting web servers and software tools for bioinformatic applications.

For more information on Dr. Guda: Website

Kyle J. Hewitt, PhD
Assistant Professor
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Our research utilizes diverse approaches to unravel essential molecular and cellular mechanisms that govern blood homeostasis, blood regeneration following injury, and genetic mutations that predispose illness. We value active hands-on training and mentoring, and expect that students develop constructive critical thinking skills to guide their individual projects. The lab is particularly interested in the function of a transcription factor, termed GATA-2, which controls for development and function of the blood system. Mutations in GATA-2 cause myelodysplastic syndrome, acute myeloid leukemia, primary immunodeficiencies, and anemia. We discovered that GATA-2 activation of Sterile α-Motif Domain 14 (Samd14)  is important for stem/progenitor cell function in regeneration, and required for recovery from severe anemia in mouse models. In addition to elucidating the function of Samd14 in hematopoiesis, our lab is discovering new GATA-2 regulated genes which are required for maximal stem cell function in regenerative contexts such as anemia and blood/cardiovascular disorders. Understanding the mechanisms that cause blood disorders and cancer is an essential step toward developing personalized medicine approaches and advancing disease treatments.

For more information on Dr. Hewitt: Website

Shantaram Joshi, PhD
Professor
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Research Interests:  Despite advances in treatment, leukemia and lymphoma are often fatal diseases in people.  Our laboratory research is concentrating on find out out in greater detail what changes occur at the molecular level in B-cell cancers of the immune system.  By determining what changes occur, especially in cells that become resistant to chemotherapy, we are trying to help design better therapy for patients.

For more information on Dr. Joshi: Website