Faculty Research Retreat 2013 - concurrent sessions
Chair and first speaker – Anindya Dutta
Introduction to state of current genomics research – discovery science, current clinical implications
ENCODE work indicates relatively few genes, but most of the genome is active – different types of RNA produced
Topic: Using ultra-high throughput sequencing to discover different types of nucleic acids and genomic information
Sequence, structural, and functional information, i.e., microRNAs (mRNA silencing), microDNAs (unknown function), tRNA fragments (cell proliferation control)
Future potential and directions
Ira Hall – DNA genomics
Extent, origin and control of structural variation in mammalian genomes
Structural variation in in genomes – normal and cancer cells
DNA from tumors suggests novel structural changes, novel oncogenes and tumor suppressors
(Current status in tumors?)
Hui Li – Trans-splicing of RNA
New fusion proteins formed by trans-splicing of RNA between genes – normal and cancer cells
Higher levels in cancer – may contribute to tumor biology
Mazhar Adli – Epigenetics in the hematopoietic system
Epigenomic studies in hematopoietic cells – as few as 10,000 cells sufficient for surveying the epigenome
Role of epigenetic changes in stem cell differentiation, cancer
Stephen Rich – Genetic variations associated with disease in human populations
Panel Discussion/Answers to Questions
Discussants: C. Moskaluk, S Turner, S Rich, M. Mahadevan
Resources at UVA – BTRF, Bioinformatics, Genomics and Clinical Partners
Session description: The objective is to highlight approaches to studying hypertension and stroke at UVA. The following items will be discussed: the importance of a partnership between clinical and basic research; ways of approaching important research questions when large numbers of patients are required for reliable answers; and the use of new technologies (e.g., genomics) to answer important research questions.
Talk 1: Overview – Helmy Siragy – Approaching the complex and the enigmatic: hypertension and stroke as prismatic examples
- Dr. Siragy will highlight the global impact of hypertension and stroke, describe some major questions and challenges, the benefits of local and national collaborations, in addition to new technologies/approaches (e.g., genomics).
Talk 2: Research – Robin Felder – Discovering the pathogenesis of essential hypertension and salt sensitivity: a multidimensional approach
- Dr. Felder is spearheading a Program Project Grant designed to investigate mechanisms of salt sensitivity as it relates to blood pressure control. They are employing a multipronged approach including molecular genetics, biochemical techniques, in-vitro, and in-vivo studies in humans (collaboration with Bob Carey).
Talk 3: Research – Karen Johnston – Approach to hyperglycemia in acute ischemic stroke: the SHINE trial
- Dr. Johnson is the National PI for the Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial is a large, randomized, controlled, multicenter (over 60 US sites) phase III efficacy trial of intensive insulin therapy versus standard care for hyperglycemic acute ischemic stroke patients (funded by the NIH-NINDS). This effort involves endocrinology and a private sector entity that has the FDA-cleared decision support tool. Dr. Johnston could potentially discuss how this multicenter study was initiated and organized, how/why she was appointed national PI, the relationship with the private sector entity mentioned above, etc.
Talk 4: Research – Bradford Worrall – Understanding the links between intracranial and abdominal aortic aneurysms
The Brain and Aortic Aneurysm Study is a collaborative research program comprising the UVA Divisions of Vascular Neurology (Worrall, Southerland), Vascular Surgery (Upchurch), and the Center For Public Health Genomics in an effort to prospectively identify the co-prevalence of intracranial aneurysms (IA) and abdominal aortic aneurysms (AAA) in our patient population. These entities (IA and AAA) share a co-prevalence in a high risk subset of the population with common genetic and environmental risk factors. The following will be performed as pilot studies: (1) aortic sonography in participants with known IA, both ruptured and unruptured; (2) non-invasive vascular imaging (CTA or MRA) in participants with known AAA; and (3) genetic screening for high-risk variants associated with aneurysm formation. This research program provides the infrastructure for an ongoing multi-disciplinary, Brain and Aortic Aneurysm Clinic, to identify and properly manage high risk aneurysm patients going forward.
Christopher Kramer – Cardiovascular Imaging at UVA: From mouse to human
An overview of the cardiovascular imaging program at UVA, with emphasis on the spectrum of imaging programs that span from pre-clinical imaging in small animals to clinical trials, with particular focus on PAD
Collaborators: Frederick Epstein, Craig Meyer, Brent French; industrial partnership: Siemens
Relevant local resources: Resources in Radiology and Cardiovascular Medicine, Molecular imaging core
Kenneth C. Bilchick – Imaging in Cardiac Electrophysiology
Explores the utility of MRI in cardiac electrophysiology, with examples of optimizing the selection of patients for cardiac resynchronization therapy.
Collaborators: Frederick Epstein, Jeffrey Holmes
Relevant local resources: Resources in Radiology and Cardiovascular Medicine, Molecular imaging core
Jason Druzgal –Neurological Imaging at UVA
An overview of the neurological imaging program at UVA, with emphasis on research infrastructure and thrust areas with the greatest potential for impact in the areas of cognitive disorders, traumatic brain injury and focused ultrasound.
Collaborators: Max Wintermark, James Stone, Jamie Morris, James Coan, Howard Goodkin, Donna Broshek
Relevant local resources: Resources in Radiology, Focused Ultrasound Center
Nicholas Tustison – Advanced neuroimaging at UVA, Imaging pipelines for neurodegenerative disorders, traumatic brain injury, movement disorders, epilepsy, stroke and brain tumors
An overview of the quantitative image analysis and computational processing capabilities for research involving imaging of small to large cohorts. Case studies involving various neuropathologies and normal development showcase some of the more prominent analysis tools currently in use at UVA and applicable to a spectrum of imaging-related research.
Collaborators: Max Wintermark, Jeff Elias, Mark Shaffrey, Jason Sheehan, James Stone
Relevant local resources: Resources in Radiology, UVA Cluster
Kimberly Kelly – Molecular Imaging of Cancer and Biomarker Discovery in Pancreatic Cancer
An overview of cancer imaging at UVA with an example of how a biomarker discovery project has shed new light on cancer biology and developed into a practical method for imaging pancreatic tumors in patients using nuclear imaging (PET & SPECT) of a targeted contrast agent.
Collaborators: Todd Bauer and Patrice Rehm
Relevant local resources: Buchanan Foundation, Molecular Imaging Core, UVA Cyclotron Facility
Overview: Thomas Platts-Mills (Chair) – The Rise in Asthma: Global Lessons in Disease Pathogenesis (Allergy)
(1) the global impact of allergic disease;
(2) current views on reasons for the rise in asthma and other allergic diseases;
(3) current views on the role of environmental microbial exposure;
(4) the contribution of new and emerging allergens;
(5) challenges to understanding the link between allergens and allergic disease;
(6) Role of international collaborations in advancing knowledge;
(7) how genomics/proteomics and emerging technologies may impact our understanding of the disease.
Peter Heymann – The Link Between Viral Infections and Asthma: Cause or Consequence?
(1) Controversies regarding the role of viruses in asthma;
(2) Challenges to studying the role of viruses in childhood disease and in later life;
(3) Lessons from studies within the U.S. and abroad;
(4) Ongoing clinical trials involving experimental rhinovirus challenge;
(5) Partnerships with industry and interdisciplinary approaches.
Gerald Teague – Challenges to Studying Severe Childhood Asthma
(1) Insights into the pathogenesis of severe asthma in children from the NHLBI Severe Asthma Research Program;
(2) Use of hyperpolarized helium-3 MRI to image the asthmatic lung and future challenges to this approach;
(3) Applications and clinical challenges of image-guided specimen collection from the young asthmatic lung.
Julia Wisniewski* – Insights into Immunology of the Young Asthmatic Lung
(1) Approaches to immunophenotyping the asthmatic lung.
(2) Describe the interdisciplinary research team and use of UVA Cores.
* Junior faculty
Speaker 1 and session organizer: Jonathan Kipnis – The role of the immune system in supporting brain function
Jonathan Kipnis is a Director of the newly established center for “Brain Immunology and Glia (BIG)” in the Department of Neuroscience at UVA. This field is interdisciplinary at its core, spanning the intersection of neuroscience and immunology. He will introduce this exploding field, discuss major recent breakthroughs, outline the challenges to be tackled, and the promise for translational advance in understanding and treating disorders of the nervous system. Examples from his own work and collaborations will be given.
Speaker 2: Alban Gaultier – Novel role for LRP1 during Experimental Autoimmune Encephalomyelitis (EAE)
Alban Gaultier is a new Assistant Professor of Neuroscience and a member of the BIG center. He works on mouse models of multiple sclerosis (EAE) and will discuss his recent insights into the mechanisms of clearance of myelin debris in the EAE brain. He has made innovative use of mass spectrometry to identify important molecules underlying the inflammatory response in EAE and to probe the roles that the innate immune system plays in the disease process. The strength of the UVA core mass spec facility will be discussed.
Speaker 3: Michael McConnell – Genetic mosaicism in human neurons
Michael McConnell is working on cutting edge research involving complex genomics, making use of human IPSCs (induced pluripotent stem cells). Even though his primary interest is in Neuroscience, his expertise is relevant to complex diseases more generally and his approaches will be of interest to a wide audience.
Speaker 4: Kevin Lee – Neuroinflammation as a therapeutic target for limiting cognitive decline after cardiopulmonary bypass surgery
Dr. Lee’s primary research interests are stroke and epilepsy and he has strong collaborative ties to clinicians and industry. He will discuss the role of neuroinflammation in cognitive decline after cardiopulmonary bypass surgery. This work is carried out in partnership with Irv Kron’s lab in the Department of Surgery.
Jason Papin – Systems biology of metabolism: applications in microbial pathogenesis
1) Provide overview of systems biology research at UVA and its relationship to other initiatives
2) Cover the application of modeling tools and high-throughput data integration for drug identification in infectious disease
Collaborations: Erik Hewlett, MD; Infectious Diseases
Relevant local resources: Biomolecular Research Facility and Bioinformatics Core
Jeffrey Saucerman – High-throughput microscopy and modeling of cardiac myocyte hypertrophy
Subject matter: Use of computational modeling to describe signaling networks critical to the validation of drug targets.
Relevant local resources: Advanced Microscopy Facility, Keck Center for Live Cell Imaging
Peter Kasson – Systems biology, cloud computing and mechanisms of infectious disease
Subject matter: Use of large-scale computing to integrate structure, dynamics and microscopy for constructing utility models of drug resistance
Relevant local resources: Advanced Microscopy Facility, Keck Center for Live Cell Imaging, ITC
Kevin Janes – Cancer systems biology: small-scale approaches to big questions
Subject matter: Systems modeling of transcriptional networks underlying cell-to-cell heterogeneity
Collaborations: Kristen Atkins, MD; Surgical Pathologist
Translational aspects: Patient stratification and response to targeted therapies
The AstraZeneca (AZ) alliance at UVA—how it formed and its current status and arrangement. The advantages and pitfalls of working with big pharma.
Translational aspects of the AZ alliance, with focus on AAA and its impact in candidate drug selection.
How the matured collaboration with Steve Rich, Center for Genomic Research, has aided the hunt for atherosclerotic gene targets in human populations.
How integration of multiple collaborations at UVA has provided novel concepts for blood pressure regulation
David Schiff: Malignant primary brain tumors, epitomized by the deadly glioblastoma, have been the beneficiaries of a tremendous increase in scientific understanding of their underpinnings but only modest therapeutic interventions. On the clinical front, our focus has been on therapeutic trials targeting angiogenesis, intracellular signaling, and immunotherapy. Advances in neuroimaging, particularly as relate to tumor metabolism, hold great promise in improving our understanding and management of these malignancies. Local delivery of therapies may allow us to circumvent the problem of the blood-brain barrier and take advantage of these tumors' lack of metastatic potential.
Roger Abounader: Receptor tyrosine kinases (RTKs) are co-deregulated in a majority of glioblastoma (GBM), the most common and deadly brain tumor. We show that RTKs c-Met, EGFR and PDGFR regulate microRNA-134 (miR-134) in GBM. We find that miR-134 is downregulated in human GBM and GBM stem cells and that it inhibits their proliferation, survival, self-renewal, stemness and xenograft growth. We identify KRAS and STAT5B as miR-134 targets. We thus establish miR-134 as a novel RTK-regulated tumor-suppressive hub mediating RTK and RTK-inhibitor effects on malignancy and stem cell pathobiology via KRAS and STAT5B. In addition to the above, our lab is working on identifying additional key regulatory microRNAs in glioblastoma. We plan to use them as therapeutic targets or agents. We are seeking collaborators with expertise in nucleic acid sequencing and bioinformatic analysis of RNAs and signaling pathways as well as experts in RNA/antisense delivery to the brain.
Richard Price: Critical challenges in treating brain cancers include overcoming radioresistance and targeting local therapies. Focused ultrasound provides one potential answer to both problems. The Price laboratory has shown that focused ultrasound has potential not only as a direct tumor-killing modality for brain tumors, but also as a means to target nanotherapies to the tumors. Microbubble-encapsulated nanotherapies can be released selectively within brain tumors via their rupture with ultrasound beams focused on the tumors, which also open up the vasculature to assist in tumor penetration. Potential collaborations could address optimal microbubble payloads, methods to address obstacles to focused ultrasound such as penetrating bone, and biophysical methods to enhance focusing of ultrasound beams.
Hui Zong: Cures for brain tumors will only be achieved when basic scientists and clinicians work together, using animal models and cell culture to probe deeply into mechanistic issues. I will present some of our recent work done with a mouse genetic mosaic model that reveals mutant/tumor cells at single-cell resolution in vivo. Using the model, we identified the glioma cell-of-origin in proneural subtype gliomas as the OPC rather than the NSC. This finding suggested a potential cellular target for therapy, but also demonstrated the importance of cell type-specific responses to oncogenic mutations for tumorigenesis. Finally I will discuss the great potential to use this mouse model to study tumor-niche interactions with living imaging methods, and to serve as a robust, quantitative pre-clinical glioma model to evaluate therapeutic effects of lead compounds for not only treatment but also prevention.
Panel Discussion: Panelists and organizer BJ Purow will discuss further the therapeutic challenges inherent in treating brain cancers such as glioblastoma, including delivery past the blood-brain barrier, need for precisely-targeted therapies within such a sensitive organ, relative radiation and chemotherapy resistance, cancer stem cells, and genetic heterogeneity. Opportunities for collaborations at UVA exist in areas such as local delivery, drug discovery, pharmacology, cell signaling, and neurodevelopmental biology.
LESSONS LEARNED ABOUT RESEARCH CAREERS FROM YOUNG AND SENIOR INVESTIGATORS
Summary: Each of our speakers will provide vignettes of science at the intersection of the human host with a microbe, with an eye towards anti-infective therapy targeted not at the microbe but at human pathways exploited by infection. In addition, the vignettes will be used to illustrate how to facilitate careers in science. This will include utilization of Cores, Centers, Training Programs, nontraditional funding mechanisms (including grants targeted to new investigators, seed funding, foundations, small business grants, intellectual property, DTRA, DIA), following where the science leads through hypothesis testing, science from the perspective of basic and clinical investigators, and finally pearls on laboratory management. We plan to call on the audience for your own thoughts on each of these topics!
Overview: Health of Impoverished Infants in the Developing World: Infection, Nutrition, Cognitive Development and Vaccine Failure.
Speaker: William Petri, MD, PhD (Chair)
Discuss: (1) Richness of longitudinal studies of human populations, with the tools improving every year for genomic, immunologic, nutritional and cognitive studies; (2) the neuroimmunology of motor and language development in infants; (3) why oral vaccines fail when they are most needed; and (4) the common ground of endocrinology, immunology and infectious diseases.
Research Talk 1: The Role of Chemokines in Host Defense Against Bacterial Pathogens (Immunology/ Biodefense).
Speaker: Molly Hughes MD, PhD
Discuss: (1) The role of chemokines in the host response to bacterial pathogens, especially in a time of emerging multi-drug resistance worldwide and fewer antibiotics to fight the war against the pathogens; (2) Work in Pakistan on bacterial pathogens (Aga Khan University); and (3) The role of partnerships with funding agencies (e.g., DoD, Gates Foundation) and collaborations within UVA and beyond.
Research Talk 2: Comprehensive profiling of a host-pathogen interface: Lessons learned from Neisseria gonorrhoeae interactions with the human immune system (Immunology/Bacterial Pathogenesis)
Speaker: Alison Criss, PhD
Discuss: (1) The cell biology, genetics, genomics, and biochemistry of how a pathogenic bacterium resists clearance by immune cells, with a goal of novel treatment options for an emerging “superbug”; (2) What happens when you let junior faculty loose: collaborations to study structure-function relationships in a variable family of bacterial membrane proteins (with L. Columbus, Dept. of Chemistry) and to investigate bacterial-immune interactions in primary human samples (with C. Warren and J. Eby, Div. of Infectious Diseases, Dept. of Medicine); (3) Pursuing (and sometimes attaining) funding earmarked for new investigators; and (4) Lessons learned about starting and growing a research laboratory.
Research Talk 3: How Structural Biology may Inform us about the Outer Membrane Barrier to Antibiotics in Gram-Negative Bacteria and Ebola Virus Entry into Mammalian Cells.
Speaker: Lukas Tamm, PhD
Discuss: (1) Defending bacteria from foreign intruders: Determination of the structures of two outer membrane proteins/pores from Pseudomonas aeruginosa by NMR. (2) Punching a whole with a fist: Structure, function, and mutational studies of the Ebola virus fusion loop. (3) Team-work is better than running circles in a silo: Establishing inter-departmental collaborations within UVa. (4) Looking beyond the horizon: International collaborations can really boost your research. (5) A case for research centers: UVa’s Center for Membrane Biology can help you!
* Junior faculty