Find a Member
Finding the right member is just a click away.
Finding the right member is just a click away.
A critical question to ask, particularly in this genomic era, is how organisms interpret the vast amounts of information encoded in their genomes. The Arndt lab studies the first step in gene expression, the synthesis of mRNA by RNA polymerase II, with a focus on the mechanisms that regulate transcription in the chromatin environment of a eukaryotic cell. The fundamental importance of understanding transcriptional regulation is evident from the large number of human developmental defects and diseases, including cancer and AIDS, that arise when cellular transcription factors are altered by mutation or commandeered by viral proteins.
My work is to determine what genetic factors make some people more likely to develop cancer, particularly breast and ovarian cancers. The genes that we study are important for fixing damage to DNA. If these genes are not operating properly and DNA damage is uncorrected, cancer may develop. DNA damage can be caused by our bodies themselves or from outside sources such as chemicals found in the environment. We are working to better predict who is likely to get cancer by understanding both people's genes and their environmental exposures. By doing so, we aim to create new tailored strategies for treating people's tumors and ultimately prevent patients from developing breast and ovarian cancers at all.
The purpose of my laboratory’s research is to investigate the effects of environmental exposure on the host. We are particularly interested in infection and immunity on the lung and its associated pathophysiological response during injury, repair, and regeneration. The primary focus of my current research is the cellular and molecular actions of exposures to toxic chemicals and microorganisms that underlie the pathogenesis of chronic human diseases. Areas of research: 1. Lung epithelial cell phenotype, differentiation, and function upon exposure; 2. Inflammation-associated tissue remodeling and lung tumorigenesis; 3. Development of novel antibiotics to overcome antimicrobial resistance (AMR).
Dr. Deborah Galson's laboratory is focused on two main areas:
(1) Determining the mechanism by which multiple myeloma (MM) cells reduce bone formation via suppression of the differentiation capacity of osteoblast progenitor cells in a manner that persists even after removal of the myeloma cells. These MM-altered bone marrow stromal cells also enhance osteoclastogenesis and microenvironmental support of myeloma growth. We have shown that myeloma cells induce the upregulation of expression of the transcriptional repressor Gfi1 in osteoblast precursor cells and that Gfi1 has a role in repressing Runx2, the key osteoblast transcription factor. We are currently investigating the mechanisms by which Gfi1 represses Runx2; MM cells and TNF-alpha/IL-7 regulate Gfi1 expression and activity; and roles for Gfi1 in MM cells and osteoclasts. Our preliminary data suggests that Gfi1 may prove to be a useful 3-way therapeutic target in MM bone disease. We are also expanding these studies into other cancer-induced bone disease models and into inflammatory diseases that cause bone formation suppression.
(2) Determining the mechanism by which measles virus nucleocapsid protein (MVNP) activates cellular genes and alters osteoclast differentiation. MVNP has been shown to be able to induce a Pagetic phenotype when transduced into osteoclast precursors and there is increasing evidence that it can play a role in the development of Paget's disease. Understanding the mechanisms involved may aid in developing additional treatments for Paget's disease as well as increase our understanding of how viral proteins alter cells. We have made the important discovery that MVNP signals through the IKK family members TBK1 and IKKepsilon to increase IL-6, a key player in creating the pagetic microenvironment. We are also studying MVNP regulation of C/EBPbeta and FoxO proteins, as well as autophagy, in generating aberrant osteoclasts. We have found that MVNP alters both the level of C/EBPbeta expression as well as the translation regulation of the C/EBPbeta LAP/LIP isoforms ratio. MVNP also alters the regulation of FoxO1 cellular localization, preventing nuclear localization, which increases autophagy, Further, MVNP alters the stability of FoxO3a, leading to rapid degradation and loss of SIRT1 expression, which thereby increases NF-kappaB activity. We are expanding the investigation of TBK1 and IKKepsilon signal transduction into other disease models that elevate osteoclasts including cancer-induced bone disease and arthritis.
Dr. Luo's research is in the area of genome and gene expression studies of malignancies, especially in understanding how prostate cancers obtain invasive and metastatic capabilities. Dr. Luo's laboratory in the past has primarily focused on the isolation and characterization of genes which are inactivated in prostate cancers. His laboratory has isolated and characterized several candidate genes that may be important for tumor invasion. Ongoing studies focus on defining the roles of these genes in regulating signaling pathways in normal and cancerous cells. In addition, his laboratory is actively searching for new candidate genes that are overexpressed, down-regulated, deleted, amplified, methylated, translocated or mutated in tumors, using Affymetrix array and whole genome and RNA sequencing technologies. His group is exploring the possibility of using these genes as diagnostic or prognostic markers for prostate cancers. On clinical molecular diagnostic front, Dr. Luo has recently initiated whole genome high throughput CNV analysis of lymphoproliferative diseases using Affymetrix array, and works to provide this information in an accurate and concise manner to clinicians involved in patient care and treatment. His group is now conducting a prospective analysis using a whole genome CNV array to predict clinical outcomes of prostate cancer.
Dr. Nikiforov's research is focused on thyroid cancer genomics and mechanisms of chromosomal rearrangements and other mutations induced by ionizing radiation in thyroid cells and other cell types. Since 2000, Dr. Nikiforov's research activities have led to four scientific discoveries. These discoveries described below have resulted in more than 120 published papers and form the basis of Dr. Nikiforov's current work. 1.The discovery that genes involved in recurrent chromosomal rearrangements in cancer cells are localized in proximity to each other in the nuclei of normal human cells at the time of exposure to ionizing radiation or other genotoxic stress (Science, 2000, 290:138-141). 2.The discovery that BRAF oncogene can be activated as a result of chromosomal rearrangement (J Clin Invest, 2005,115:94-101). 3.The discovery that in thyroid cancer, chromosomal rearrangements represent the main mutational mechanism in tumors arising as a result of exposure to ionizing radiation, whereas point mutations are a mechanism of spontaneous (chemical) carcinogenesis (J Clin Invest, 2005,115:94-101). 4.The discovery of ALK activation in thyroid cancer as a result of STRN-ALK fusion (PNAS, 2014, 111:4233-8). Current research activities of Dr. Nikiforov's lab are focused on further understanding the molecular mechanisms of radiation-induced carcinogenesis and chromosomal rearrangements in human cells. Specifically, the studies aim to establish the number of double-strand DNA breaks required for the formation of a chromosomal rearrangement after exposure to ionizing radiation and identify the DNA repair mechanisms involved in this process. The results of this research will allow better understanding of carcinogenesis induced by ionizing radiation and help to develop measures for alleviating and preventing the carcinogenic effect of radiation exposure. Another direction of Dr. Nikiforov's research is centered on finding novel mutations and gene fusions in thyroid cancer using next-generation sequencing and applying the current knowledge in molecular genetics of thyroid cancer to the clinical management of patients with thyroid nodules. Specifically, the studies in progress aim to define the diagnostic utility of molecular markers for preoperative diagnosis of cancer in thyroid fine-needle aspiration (FNA) biopsies and to characterize several novel chromosomal rearrangements discovered in thyroid cancer by next generation sequencing.
The immediate goal of our research is to understand how anticancer drugs kill cancer cells, and more importantly, why they fail so often. In the long term, we will attempt to use this knowledge to identify novel molecular targets and treatment strategies to improve cancer chemotherapy and chemoprevention. Cell Death in Anticancer Therapies Our research program has centered on several molecules that control discrete steps of programmed cell death. The first one, PUMA, is a downstream target of the tumor suppressor p53 and a BH3-only Bcl-2 family protein. PUMA is required for DNA damage-induced and p53-dependent apoptosis, and also plays a key role in apoptosis induced by several targeted anticancer drugs. The second one, SMAC, is a mitochondrial apoptogenic protein and a caspase activator. SMAC helps to execute apoptosis induced by anticancer drugs via a mitochondrial feedback loop. Regulators of non-apoptotic cell death, such as the autophagy inducer Beclin 1 and the necrosis regulator RIPK3, have also been studied. Through analyses of these molecules and their associated protein networks, we try to gain deep understanding on how cell death is initiated and executed in human cancer cells, why some cancer cells are not sensitive to anticancer drugs, and what can be done to restore their sensitivity. Oncogenic Stem Cells as the Target of Cancer Chemoprevention Prevention of human cancer through the use of chemical agents such as non-steroidal anti-inflammatory drugs (NSAIDs) has emerged as a promising strategy to reduce morbidity and mortality of cancer. Our recent studies showed that intestinal stem cells that have acquired oncogenic alterations are targeted by NSAIDs in chemoprevention of colon cancer. We are investigating how NSAIDs trigger apoptosis in such oncogenic stem cells, and if induction of apoptosis is critical for the chemopreventive effects of NSAIDs. We will also determine if apoptosis regulators can be used as markers to predict outcomes of chemoprevention of cancer patients, and if manipulation of apoptosis regulators can be used to improve the chemopreventive effects of NSAIDs. Manipulation of Cell Death Regulators To target PUMA, we have developed a high-throughput screening system for identifying small molecules that can activate PUMA in p53-deficient cancer cells. In collaboration with the UPCI Chemical Biology Facility, we will screen compound libraries to identify novel PUMA inducers. We have also identified and characterized small molecules that mimic the functional domains of PUMA and SMAC. Efforts are undertaken to apply these small molecules to chemotherapy and chemoprevention.