520 Bridgeside Point 2
Millions of people are infected with both HIV and HBV. Morbidity and mortality in HIV/HBV co-infection is higher than mono-infections and co-infection accelerates HBV-related liver disease with more frequent development of hepatocellular carcinoma (HCC), particularly when CD4 cell counts are low. Together with Dr. Haitao Guo, we will develop a murine model to study pathogenesis and HCC progression during HIV/HBV co-infection, which will be essential in evaluating mechanisms of infection as well as novel prevention methods, improved therapies, and curative strategies.
130 DeSoto Street
- liver disease
- innate immunity
- macrophage activation
- humanized mouse models
5117 Centre Ave Suite 1.8
- Tumor viruses
- Kaposi's sarcoma associated herpesvirus (KSHV)
- Merkel cell polyomavirus (MCV)
- digital transcriptome subtraction
- tumor virus discovery
The work of our group (jointly directed by Patrick Moore and Yuan Chang) has focused on human tumor viruses since the early 1990s when we identified Kaposi's sarcoma associated herpesvirus (KSHV/HHV8) and showed that this virus was causally associated with Kaposi's sarcoma, the most common AIDS-related cancer in the United States and the most common malignancy in parts of Africa. We sequenced the KSHV genome, developed serologic assays, determined its prevalence in human populations, and characterized many of its critical viral oncoproteins. We have continued to study virus-host cell interactions in the context of dysregulation of pro-proliferative and anti-apoptotic pathways. We recently identified the seventh human tumor virus, Merkel cell polyomavirus (MCV), from a Merkel cell carcinoma (MCC). We characterized the transcriptional products of MCV and described the early region viral T antigen oncoproteins. Our work has established that MCV causes ~80% of MCC: we determined that the virus is clonally integrated in MCC tumor cells; that human tumor-associated Large T (LT) antigens contain signature truncation mutations; that T antigen proteins are expressed in MCC tumor cells by novel antibodies we developed; and we are the first laboratory to show rodent cell transformation by MCV sT antigen but not the LT antigen. We have identified several novel cellular interactors for MCV T antigens that open new avenues of investigating critical oncogenic signaling pathways. We have focused on many aspects of cancer etiology as modeled through oncogenic tumor viruses.
- HSV vectors, glioblastoma, chronic pain
Dr. Glorioso has spent his career studying the molecular biology of HSV and the last 20 years developing HSV gene vectors. He is a world-wide leader in this field and has to the expertise to develop the technology related to the treatment of diseases of the peripheral and central nervous system. His interest in peripheral nerve disease has included nerve degeneration due to diabetes and cancer drug therapies that have led to treatments of animal models. Studies to understand the pathophysiology of chronic pain and the identification of gene therapy interventions that create effective pain therapies have been long standing interests and he was among the first to develop HSV vectors to treat pain. This research has culminated in clinical trials for treatment of cancer pain. Dr. Glorioso has also focused his attention on neurodegenerative diseases that include SCA1 and Huntington's disease and the development of oncolytic vectors to treat brain tumors. Part of this research extends his application of HSV vectors for vector delivery across the blood brain barrier and for targeting specific neuronal cell populations in animals. He has also recently developed HSV vectors for the creation and neuronal differentiation of human iPS cells derived from fetal brain and human fibroblasts.
- Structural biology
- gene regulation
- HIV pathogenesis
- nuclear magnetic resonance spectroscopy
- protein folding
Research in my lab combines nuclear magnetic resonance (NMR) spectroscopy with biophysics, biochemistry, and chemistry to investigate cellular processes at the molecular and atomic levels in relation to human disease. We presently focus on two areas in biology: gene regulation and HIV pathogenesis. To understand how biological macromolecules work and intervene with respect to activity and function, detailed knowledge of their architecture and dynamic features is required. Evaluation of the major determinants for stability and conformational specificity of normal and disease-causing forms of these molecules will allow us to unravel the complex processes associated with disease. Our group has developed new NMR methods for determining three-dimensional structures of biological macromolecules and applies these to challenging systems. Key contributions include the development of restrained molecular dynamics/simulated annealing algorithms and multidimensional, heteronuclear spectroscopy, which allowed the extension of conventional NMR methods to higher molecular weight systems. Our group has solved solution structures of a large number of medically and biologically important proteins, including cytokines and chemokines, transcription factors and their complexes and various HIV and AIDS related proteins. Work is also carried out on protein folding and design using the model protein GB1.
450 Technology Drive
- Herpes simplex virus type 1 (HSV-1)
- capsid assembly
- DNA packaging
5117 Centre Ave.
In my role as leader in AI for Cancer Research, I work closely with Hillman PIs and Hillman leadership to develop the AI infrastructure and capability to advance clinical operation, clinical research, and basic cancer research. I envision building a robust AI capability at Hillman that can meet the AI needs for cutting-edge cancer research and be adapted to address new challenges. My current cancer-related research includes:
1. Mechanism of infection and oncogenesis by KSHV
Goals: Using a combination of bioinformatics/machine learning, high throughput profiling (scRNA-seq, in-situ-seq, 16s-seq, etc), and bench experiments to delineate the mechanism of KSHV-induced cellular transform and oncogenesis, elucidate pathogenesis of KSHV-associated cancers, and identify effective therapeutic targets and prognostic biomarkers. I have collaborated with Dr. SJ Gao and together have identified targets and pathways regulated by KSHV miRNAs (Nat. cell Biology, 2010), delineated the addicted cellular genes and networks by genome-wide CRISPR-Cas9 screening (MBIO 2019), performed the first genome-wide viral and cellular m6A profiling in multiple KSHV-infected systems (Nat. Microbiology 2018), and identified the signatures of oral microbiome in HIV-infected individuals with oral KSHV (PLOS PATHOGENS, 2019).
2. m6A mRNA modification/epitranscriptome and cancer
Goals: Using a combination of bioinformatics/machine learning and high throughput profiling technologies to 1) understand the mechanisms by which m6A regulates cancer and viral infection; 2) identify m6A related clinical makers. m6A/epitranscriptome is a new and rapidly advancing area that studies modifications in mRNAs. My lab leads the development of the computation tools for analyzing m6A profiling data and predicting m6A functions. The analysis pipeline for m6A sequencing, exomePeak, is being used widely and cited > 200 times (Google scholar) since 2015 by many high impact papers in Cell, Cell Stem Cel, Nature, Nature Cell Biology, Nature Neuroscience, Nature Genetics, and Cancer Cell. Using these tools, I have collaborated with Dr. Gao and other researchers to uncover new regulatory roles of m6A in regulating KSHV infection and breast cancer progression.
3. Functional interpretable deep learning models for cancer genomics
Goals: Develop novel deep learning models that can 1) perform phenotype predictions and, at the same time, 2) identifying markers and generate explainable mechanisms. Part of this project is funded by CPRIT (Cancer Prevention and Research Institute of Texas). We have developed several genomics-based deep learning/AI tools for cancer prognosis and survival analysis, drug response prediction, and gene dependence prediction (in silico CRISPR; Science Advances, 2021).
203 Lothrop Street, Room 1016
- herpes simplex virus
- viral infection
- viral latency
- infectious eye disease
- pain and post-herpetic neuralgia
- neuronal infection
Starzl Biomedical Science Tower 200 Lothrop Street
- infectious disease animal modeling
4249 Fifth Avenue
- Simian virus 40 (SV40)
- T antigen
Lab 1.7 5117 Centre Avenue
- RIG-I-like receptors (RLR)
- interferon (IFN)-stimulated genes
- toll-like receptor 3 (TLR3)
- innate immune signaling
- anti-viral innate immunity
- type I IFN; IFN signaling
- IFN regulatory factor 3 (IRF3)
- tumor microenvironment
Innate immunity of an organism is the inborn protection against invading pathogens. Because it is inborn, and entrusted with the protection of the host from a vast array of previously unknown invaders, the innate immune system generates a generalized alert response upon pathogen detection. This alert is chemically mediated by a class of molecules called cytokines, such as interferons. A critical task for this host protection system is to distinguish foreign or non-self, from self, and initiate their destruction or containment. The sensors or the receptors of the innate immune system accomplish this by recognizing specific molecular patterns, which are common to pathogens or pathogen associated molecules, but absent in the host. We focus on a particular subset of these sensors/receptors, which are involved in sensing virus infection. In order to protect the host from viral invasion, the innate immune system has evolved sensors to detect foreign nucleic acids. Several unique features of virally produced DNA or RNA are exploited to distinguish viral nucleic acids from that of the host. One such unique nucleic acid is double-stranded RNA (dsRNA) ' a common byproduct or intermediate in viral genome replication. In mammals, receptors like toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5) are the three known sensors of dsRNA. Single-stranded viral RNA is sensed by toll-like receptors 7 and 8 (TLR7 and TLR8), while viral DNA is detected by toll-like receptor 9 (TLR9) and other cytoplasmic receptors. We study two related aspects of the signaling process involved in interferon production in the context of infectious disease and cancer: 1) modulation of viral RNA sensing mechanisms; and 2) alternative mechanisms of interferon induction in specific tumors.
450 Technology Drive
- Protein-tyrosine kinases
- Src-family kinase
- drug discovery
- chemical biology
Scaife Hall S701 200 Lothrop Street
- Viral infection
- innate immune response