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A fundamental question in molecular biology is how organisms interpret the vast amounts of information encoded in their genomes. The Arndt lab uses a wide range of experimental approaches to study 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. Specific areas of interest include the mechanisms that couple histone modifications to active transcription, the coordination among different epigenetic modifications and their impact on transcription elongation and termination, and the molecular functions of core RNA polymerase II elongation factors with broad and conserved effects on the eukaryotic transcriptome. The fundamental importance of understanding eukaryotic 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.
Radiation therapy and many chemotherapies induce DNA damage. These therapies work because cancer cells divide more rapidly than normal cells and cancer cells acquire mutations that change their DNA damage responses and DNA repair mechanisms. Nevertheless, radiation and DNA damaging chemotherapies may not generate long-term responses as the dose of DNA damage required to kill all cancer cells may kill too many normal cells – dose limiting toxicity. The Bakkenist Lab studies how pharmacologic DNA damage response inhibitors can be used to increase the damage induced in cancer cells and potentiate anti-tumor immune responses. Our long-term goals are to develop new therapeutic approaches to manage human cancer.
Visit the Bakkenist Lab Website to learn more.
Research in the Brieno-Enriquez lab focuses on the regulation of gametogenesis in human and mouse and, more specifically, the fundamental mechanisms that are required to produce viable germ cells. Our studies include the analysis of all the different stages of germs cells including primordial germ cells (PGCs), spermatocytes, oocytes, as well as how age affects them. Our long-term goal is to test our overarching hypothesis that gene expression, epigenetic clock, and chromatin structure in the naked mole-rat can be hijacked for use in other species, allowing us to regulate the establishment and maintenance of the ovarian reserve, oocyte quality, and reproductive longevity.
Our work focuses on understanding: (1) how misfolded proteins are recognized and destroyed in normal and tumor cells, (2) how molecular chaperones mediate protein quality control “decisions”, (3) how protein quality control pathways can be targeted in disease models, and (4) how cellular stress responses (such as the Unfolded Protein Response, UPR) affect protein biogenesis and homeostasis, especially in cancer. The pursuit of these goals has employed biochemical, cell biological, and genetic tools using a range of models, including yeast, cell culture, and rodents. Our early work contributed to the discovery of the ER associated degradation (ERAD) pathway, which we named, and ongoing studies are deciphering the mechanisms underlying the ERAD pathway in yeast, mammalian cell culture, and rodent models, and its relationship to cellular stress responses. The importance of ERAD is underscored by the fact that >70 human diseases—including several cancers—are associated with this pathway. In parallel, new classes of small molecule modulators of chaperones and the ubiquitin-proteasome pathway have also been isolated, which we have used to probe the relationship between stress responses, protein homeostasis (“proteostasis”), and tumorigenesis. Ongoing work has capitalized on several of our tools and areas of expertise, including (1) an analysis of protein degradation pathways and the ubiquitin-proteasome system in breast and ovarian cancer, (2) the use of small molecules and drugs to target cancer vulnerabilities, and (3) measurements of cellular stress pathways in breast and ovarian cancer.
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. Valerian E. Kagan is one of the world’s recognized leaders and one of the most prominent authorities in the field of Free Radical Biology and Medicine. Internationally known for his profound interdisciplinary studies of oxidative stress, antioxidants, tissue, and cell acute and chronic injury, he has founded a new field of research “Oxidative Lipidomics” and demonstrated its research power in investigations of cell death mechanisms. Free radicals, lipid peroxidation and oxidative stress have been long associated with tissue and cell damage through yet not well characterized specific mechanisms. The incompleteness of this knowledge is a stumbling block in discovery, development and effective implementation of antioxidant preventive and therapeutic strategies. The research performed by Dr. Kagan is a breakthrough in the field as it uncovers specific pathways through which enzymes of oxidative metabolism participate in the production of specific oxygenated lipid molecules that act as signals triggering cell death program as well as mechanisms involved in clearance of damaged or dead cells. Understanding these key signaling pathways is of prime importance for obtaining new insights into mechanisms of radiation injury, inflammation, and immune responses. Based on the discoveries of Dr. Kagan’s lab mechanism-based approaches to creation of novel generations of preventive, protective and mitigating small molecule drugs have been developed that are being tested in a number of conditions.
The Liu Lab studies several medically important bacterial virulence factors, including anthrax toxins, in bacterial pathogenesis. Through investigating the interactions of these protein toxins and their mammalian hosts, we are interested in discovering the toxins’ molecular targets and understanding the molecular mechanisms of pathophysiology. We study how these toxins alter key signal transduction pathways, in particular the RAS and ERK pathways, in cancer cells and tumor stromal cells, and we use the knowledge obtained to design and develop novel bacterial toxin-based anti-tumor drugs with high tumor specificity. We are also interested in using this approach to design and develop novel biological-based therapeutics to selectively eliminate senescent cells.
The laboratory of Dr. Yang Liu focuses on developing multiscale optical microscopy techniques spanning seven orders of magnitude, bridging the nanoscale to the mesoscale, to significantly advance precision medicine such as early detection, prevention, and treatment of cancer. The technologies integrate label-free quantitative phase imaging with hyper-plex mesoscale microscopy, super-resolution fluorescence microscopy, and highly sensitive and specific across-the-scale imaging probes, which are paired with artificial intelligence (AI), robotic automation, and large-scale image informatics. This transformative approach allows for dynamic high-content phenotyping and provides invaluable insights into the molecular changes under complex tissue microenvironments. This is critical in understanding the progression from precursors to invasive cancer and deciphering the mechanisms behind therapeutic resistance. The fusion of cross-scale imaging with AI-driven systems biology and automation is poised to drive future scientific discoveries and transform personalized medicine.
Dr. Luo's research is in the area of genome and gene expression studies of malignancies, especially in understanding how liver and 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 liver and prostate cancers. His laboratory is currently focusing on characterizing oncogenic fusion genes in human malignancies and developing fusion gene targeting tools to diagnose and treat human cancers. Dr. Luo is also interested in developing long-read sequencing techniques to characterize isoform switches and mutation isoform expressions in human cancers.
CENP-A is a heritable epigenetic mark that determines centromere identity and is essential for centromere function. Centromeres are the central genetic element responsible for accurate chromosome segregation during cell division, and as such, they are anticipated to be evolutionarily stable. How centromeres evolved to allow faithful chromosome inheritance on an evolutionary timescale despite their epigenetic maintenance is unclear. One of our interests is understanding whether CENP-A is capable of precisely and stably specifying human centromere position throughout cellular proliferation. To investigate the positional stability of human centromeres as cells proliferate, we use a fibroblast cell line that harbors a neocentromere (epigenetic stable acquisition of a new centromere at a new chromosomal site).
Studying human centromeres epigenomics is challenging since human centromeres are found at unique DNA sequences, termed a-satellite, that is highly repetitive. Another research interest of our lab is tackling this challenging DNA and the histones and proteins bound to it, by using novel epigenomics tool such as DiMelo-seq that is a long-read, single-molecule method for mapping protein–DNA interactions genome wide. This method is essentially ChIP-seq on long-reads DNA sequences that can be sequenced using Oxford nanopore long-read sequencing. We are excited to determine the centromeric DNA sequences associated with different centromeric proteins across the cell cycle and how these may change when centromeric proteins are highly expressed, as seen in cancer, using this method.
CENP-A is highly expressed in several cancers, serving as a marker of poor prognosis. When overexpressed, CENP-A is ectopically loaded onto non-centromeric transcriptionally active sites. Ectopic CENP-A sites are removed during DNA replication to restrict CENP-A to the centromeres only, ensuring faithful chromosome segregation during mitosis and maintenance of genome stability. Induced overexpression of CENP-A in cancerous cells has been shown to lead to chromosome segregation defects and micronuclei formation. Whether the sole overexpression of CENP-A in non-transformed near-diploid cells can induce genomic instability that can drive tumor formation remain poorly understood and is another focus of our lab research.
The main interest of the Neumann laboratory is to expand our knowledge of cell signaling that is in part mediated by oxidation and reducing (redox) reactions as reactive oxygen species (ROS) deregulate the redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks that cause tumorigenesis, including breast cancer. To investigate the specific mechanisms underlying redox-induced tumorigenesis, the Neumann laboratory focuses on the redox-induced posttranslational modifications (PTM) of protein cysteines, which are essential in cell signaling. Peroxiredoxin 1 (PRDX1) is a peroxidase that has emerged as a critical protein in cell signaling as it scavenges the second messenger H2O2, binds to and regulates signaling proteins, and when knocked out in mice, causes a variety of cancers, including breast cancer.
Using this system, we have identified protein cysteines modified by ROS, contributing to breast cancer initiation and progression. For example, we have discovered that a previously unknown functionally essential cysteine in the recombinase RAD51 is vital for its function in homologous recombination-mediated DNA repair. Based on these findings, we have developed a reversible, non-toxic covalent inhibitor that targets this functionally essential RAD51 cysteine, thus inhibiting RAD51 function and, significantly, sensitizing triple-negative breast cancer cells to DNA-damaging therapies. Current work in the laboratory is geared towards successfully IND-labeling the inhibitor and further discovering other functional protein cysteine targets that can be exploited as anti-cancer therapies.
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 O’Sullivan lab at UPMC Hillman Cancer Center conducts research into proteins that alter the structural and epigenetic functions of human telomeres. Telomeres are structures at the ends of chromosomes – the integrity of telomeres is an important factor in maintaining genome stability to prevent cancer and accelerated aging. Current efforts in the lab relate to: (i) deciphering the relationship between the regulation between chromatin structure and telomere function and (ii) new aspects of ADP-ribosylation in genome stability.
My lab studies DNA damage and repair at telomeres. Telomeres are the caps at chromosome ends that are essential for preserving the genome. When chromosomes lose their telomere caps the cells age and this contributes to the onset of degenerative diseases with aging. If chromosomes lose their telomere caps in pre-cancerous cells, then this causes genetic alterations that hasten the progression to cancer. Understanding mechanisms of telomere damage and repair should lead to new intervention strategies aimed at preserving these regions of the genome that are so critical for protecting our chromosomes and maintaining youthful cells. Conversely, we aim to leverage new findings to develop therapeutic strategies that deplete telomeres in cancer cells to prevent them from dividing.
Heath D. Skinner, MD, PhD, is a Professor in as well as the Chair of the Department of Radiation Oncology at the University of Pittsburgh and UPMC Hillman Cancer Center. In addition to his leadership and clinical duties, Dr. Skinner maintains an active, translational research laboratory focused upon identifying novel, clinically targetable biomarkers of resistance to radiation. His group utilizes "big data" approaches to clinical specimens as well as in vivo screening techniques to generate novel targets for study. These targets are then further investigated in vitro, to elicit insights regarding mechanisms of radioresistance. Dr. Skinner's research is designed to generate insights that led to the rational design of clinical trials using agents that are currently under investigation to minimize the time from bench to bedside. In addition to several current R01 grants, he is PI (along with Dr. Robert Ferris) of the UPMC Hillman Cancer Center Head and Neck SPORE.
Dr. St. Croix is a tenured Professor of Cell Biology and an Associate Director of the CBI. She has been a PI or co-I on NIH-funded R01s, P01s and R21s, and has been continuously funded by the NIH since 2005. A major focus of the St. Croix laboratory is the use of advanced optical imaging technologies to dissect molecular signaling pathways controlling vascular function in rodent and zebrafish model systems of disease. Within the CBI, Dr. St Croix manages and directs the use and application of fluorescence-based optical microscopy with an emphasis on advanced tools multiparametric live cell microscopy, focused light intravital small animal imaging, super-resolution microscopy methods and complex image processing.
Our laboratory studies the formation and repair of DNA damage in nuclear and mitochondrial genomes. We are particularly interested in the structure and function of proteins that mediate DNA repair and the role of oxidative stress in human disease. We use state-of-the-art single molecule, biochemical and cell biology tools.
Dr. Wang’s primary areas of research interest include design and statistical analysis of clinical trials and pre-clinical studies, and correlated survival analysis. Other areas of interest include microbiome data analysis, statistical analysis of Multiplex Immunofluorescence (mIF) data, and in vitro and in vivo radiation survival analysis.
As a Research Associate Professor in the Department of Biostatistics, and Biostatistician and former Interim Director of UPMC Hillman Cancer Center (HCC) Biostatistics Facility, Dr. Wang has been collaborating with HCC medical investigators since 2004 by leading the statistical support of the Skin Cancer, Radiation Oncology, and Prostate/GU program. He has designed over 70 clinical trials. He has been working as a statistical reviewer for UPMC HCC PRC since 2006. He is the Co-Director of Biostatistics/Bioinformatics Core for Melanoma SPORE, and lead statistician for the NCI ETCTN trials Pittsburgh consortium. He has mentored 3 GSRs and advised 2 MS students.
Optical Microscopy has formed the core of my research career since my graduate training in England. In the CBI which I founded and direct, we build, test, and use cutting edge optical tools for all types of research microscopic imaging in cells, tissues and animals from the single molecule to the whole animal, the goal being to build highly flexible, maximally effective imaging solutions, to be used by academic researchers. In fact a major focus of my career and of the Center is to develop, train and imbue researchers at all levels (undergraduate, student, post-doc and faculty) with a solid understanding (both theoretical and practical) of the power of microscopy. As a professor of Cell Biology a major focus of my research has been to develop, build, and apply computer aided microscopes and analysis tools for imaging subcellular events at all levels of resolution within fixed and living systems. These include high speed Total internal Reflection Fluorescence microscopes able to image at 100 frames/second, high speed confocal systems able to collect multicolor 3D stacks in the second timeframe and other prototype confocal systems able to scan very large tissue sections with submicron resolution at very high speed. Most recently we have been developing very high speed deep tissue imaging solutions to collect quantitative images at the diffraction limit of entire tissues including brain, and building automated multi-spectral upright solutions combined with deep learning methods to dissect spectrally complex multiplex samples, including novel approaches for studying collagen organization in large tissue volumes.