Dean's Newsletter
Archive of previous newsletters
CTSA Faculty Awards: Novel Methodologies
July 12, 2007
I am often asked what it means when I say that the Clinical and Translational Science Award (CTSA) is an "infrastructure" grant. If there is no specific research aim for the grant, what exactly does it do? One important answer is that it supports training. In the March 20th newsletter, I summarized the K12 awards within the CTSA that support faculty career development and T32 awards that support medical and graduate student research. It is hoped that these individuals, who are now students or junior faculty, will become our future independent investigators.
Another benefit of the CTSA is that it supports exploratory research on novel methodologies, as well as more traditional pilot projects, in order to generate data to obtain larger grants. This is a 2-part newsletter in which these CTSA awards to faculty will be summarized—novel methodologies this week and pilots next week.
As defined by NIH, the overall purpose of the CTSA nationally is to provide resources and develop methodologies intended to overcome the two major roadblocks to research translation: one at the discovery phase (translation between bench and bedside) and the other at the implementation phase (translation between bedside and broad community practice). Overcoming these roadblocks will accelerate the translation of our burgeoning basic science discoveries into new clinical treatments.
The development of novel methodologies concerns itself predominantly with the first roadblock, although novel approaches to overcoming the bedside-to-community roadblock will also be encouraged. Thus, original research on novel methodologies for translational and clinical sciences is a critical component of the Clinical and Translational Science Institute (CTSI) and, by extension, of URMC’s overall strategic plan for research.
By way of background, The University of Rochester Medical Center, and its School of Medicine and Dentistry, has been a leader in the development of novel clinical and translational methodologies. A few of the many examples of this type of research include:
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John Frelinger, PhD |
Systems for large-scale screening of human pathogens for T cell epitopes are being developed by John Frelinger, PhD. These new methods exploit the remarkable efficiency of micro-bead-based particulate antigen delivery, which are coupled with large-scale sequencing of pathogenic organisms and the subsequent development of directed expression libraries, to encompass all of the proteins of an organism. Translation to humans is being accomplished using model antigens such as those derived from influenza.
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Jeff Bazarian, MD |
A serum biomarker for axonal injury after concussion is being developed by Jeff Bazarian, MD, using diffusion tensor imaging and proteomic technology. This is a cross-disciplinary project that involves investigators in emergency medicine, radiology, psychology and neuroscience. As part of the proteomic component of this approach, Dr. Bazarian and his colleagues are exploring the association of a variety of serum markers (e.g., S100b, cleaved-tau, and NF-L levels) after head injury with abnormal head CT scans and with the results of neuropsychological studies.
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Clement Ren, PhD |
Several investigators (Clement Ren, PhD, Edward Walsh, PhD, Ann Falsey, PhD) are using novel techniques for measuring inflammatory mediators in exhaled air condensates, allowing non-invasive sampling of the lower airways. This has become an integral part of asthma clinical research, and is rapidly moving to the forefront of the study of the pathogenesis of a variety of viral respiratory pathogens in humans as well.
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Eun–Hyung Lee, PhD |
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Tim Mosmann, PhD, P.I. |
Flourispot assays for measurement of cells secreting multiple cytokines simultaneously, and luminex methodologies for multiple cytokine determination, are being developed in the Human Immunology Center (Tim Mosmann, PhD, P.I.). These methods are being used by Edward Walsh, PhD and Eun–Hyung Lee, PhD to evaluate primary T cell responses to respiratory syncytial virus infection in young infants. A great advantage of this methodology is that it allows detailed measurements on very small blood samples suitable for infants.
Another novel methodology with a pediatric emphasis is being developed by Clement Ren, MD and his colleagues. Although measurement of pulmonary function in adults is well established, these techniques are not suitable for use in very young infants. Investigators in Pediatric Pulmonary Medicine have developed technology suitable for measuring lung function in preschool-aged (3-6 y/o) children and are developing an infant pulmonary function laboratory. These techniques can be applied in the clinic or even in the home, and should greatly facilitate clinical studies of lung development and interventions in prematurity and cystic fibrosis.
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Dongwen Wang, PhD |
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Geoffrey Williams, PhD |
Computer software that uses internet-based behavioral interventions is being designed by Amneris Luque, PhD and Dongwen Wang, PhD to improve compliance of clinicians with HIV care guidelines. These investigators have also developed software that improves compliance of study subjects with protocol interventions.
"Real-Time" data assessment methods are being developed by Geoffrey Williams, PhD, and his colleagues utilizing hand-held devices that transmit data from home multiple times per day. This approach is particularly useful for studies of medication side effects and psychological scales for mood and symptoms. It could be applied more widely for any clinical trial that requires frequent reporting of symptoms normally collected retrospectively through the use of diary cards or memory aids.
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Edward Schwarz, PhD |
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Regis O’Keefe, PhD |
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Hermut Land, PhD |
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Andrei Yakovlev, PhD |
One of the main challenges for translational biomedical research is the need to develop rational approaches to the identification of disease-specific drug targets suitable for therapeutic application. This task is notoriously difficult and unpredictable because cell regulation is complex, and cell behavior is controlled by multiple signaling inputs. Investigators in the Departments of Biomedical Genetics and Biostatistics and Computational Biology (Hermut Land, PhD and Andrei Yakovlev, PhD) are integrating experimental and computational approaches for rational discovery of disease-relevant targets based on perturbation of multiple genes affecting the biological response of interest and mathematical modeling of gene networks.
Investigators at the Center for Future Health are developing prototypes of "ambient health monitoring" technologies that become an invisible part of the user's environment and aggregate information in a private personal health record. These technologies are being tested as health assessment tools applicable at all life stages from infancy to old age.
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John Treanor, MD |
So these are some examples of what is going on already. What about the further development of novel methodologies? The Directors of this component of the CTSA are John Treanor, MD and Eddie Schwarz, PhD. Their plan for the promotion of novel methodologies under the CTSA was to: (1) release a "Request for Proposals"; (2) organize and convene a Methodology Review Panel on a quarterly basis; and (3) hire an administrator to manage the grant reviews. Success has been achieved on all three fronts. The RFP was released on January 2, 2007. An 18 member committee has been organized with 9 standing members and 9 ad hoc members; the first meeting was held on April 16th, 2007. And we welcomed Nicole Murray to administer the CTSA’s novel methodology grants on 5/1/07.
In response to the January 2nd RFP, 28 proposals were received and14 met the criteria for further review by the committee. A Study Section reviewed the proposals in detail and met to rank them during the week of April 16. Three awards received similar high scores. Although only two awards were budgeted for this round, we asked our folks with the green eyeshades to be creative in providing a mechanism to fund all three awards. This stretched the budget, but we believe for good reason, as I hope you will agree from the summaries below.
Novel Methodology Projects funded by the CTSA, Round 1
1. Potent Lipid Mediator Measurement Methodology
Investigators: Robert C. Block, MD, MPH, Steve N. Georas, MD, Alan Friedman, PhD, (University of Rochester) and J. Thomas Brenna, PhD (Cornell University)
Dates: May 1st, 2007 – April 30th, 2008
Brief Description of Project: This project will develop new assays for a variety of potent lipid mediators in a variety of human diseases, most notably (at first) heart disease and asthma. The accurate measurement and analysis of complex lipids is emerging as an important field in biomedical science. Although still in its infancy compared to other analytical disciplines, "lipidomics" is gaining momentum. For example, the NIH funded Lipid Metabolites And Pathways Strategy (LIPID MAPS) is providing an unprecedented picture of cellular lipid metabolism, cataloging several thousand structures (www.lipidmaps.org). Lipids are increasingly recognized for their role as potent mediators in the resolution of inflammation, cell growth, signal transduction, tissue protection and homeostasis.
Two examples at SMD: (1) Dr. Block is investigating the role of the "resolvin and protectin" family of lipids in patients with heart disease, testing the hypothesis that commonly used medications in patients with coronary artery disease, such as statins and aspirin, exert beneficial effects by generating the production of these lipid mediators; (2) Dr. Georas is exploring the role of the lipid mediator lysophosphatidic acid and its receptors in asthma. This compound is detectable in bronchoalveolar lavage fluids and may contribute to the resolution of allergic inflammation. Although other "-omic" technologies are well established at SMD, there is an absence of local expertise in measuring complex lipids. The goal of this proposal is to help establish this technology on-site.
2. Arrayed Imaging Reflectometry-Based Detection of Circulatory Peptides in Prostate Cancer
Investigators: Manish Kohli, MD; Benjamin L. Miller, PhD.
Dates: May 1st, 2007- March 30th, 2008
Brief Description of Project: This proposal represents a collaborative effort to develop a novel diagnostic system for detecting and quantitating candidate pathway-specific biomarker proteins in prostate cancer. Drs. Kohli and Miller built on two unique resources developed in their laboratories: (1) a new chip-based diagnostic platform (Arrayed Imaging Reflectometry, or AIR) that can quantitatively detect concentrations of proteins with a sensitivity comparable to ELISA, but with significantly greater speed and lower cost; and (2) a bank of high quality blood and urine specimens collected from prostate cancer patients for the specific purpose of biomarker development. At present this on-going repository has collected over 350 samples of plasma and urine specimens on 200 unique subjects in four groups of prostate disease that are readily available for biomarker testing. The four research groups include (i) a control group of subjects with elevated PSA and without cancer; (ii) subjects diagnosed with local stage disease; (iii) subjects with rising PSA after primary prostatic therapy and (iv) patients with progressive disease during androgen deprivation therapy. Serial sampling is performed once every three to four months in all four groups, and serum/plasma from blood along with urine is stored at -80 °C.
AIR is a biosensor platform that enables the detection of any probe/target system by optically sensing molecular binding on a silicon chip. As a label-free technique, the assay procedure can be completed in less than 30 minutes, with nearly instantaneous readout. Comparable labeled techniques such as ELISA requires processing time of more than 2 hours. The AIR method is also amenable to multiplexing, potentially allowing 100s of different probes to be arrayed on the chip surface for simultaneous detection. In this first phase of biomarker development, Drs. Kohli and Miller will focus on the production of a chip capable of detecting several candidate angiogenesis and bone biochemistry biomarker proteins in patients with prostate cancer and controls, using specimens from the clinical groupings described above.
3. Using Heavy Water in vivo Labeling to Measure Human Proliferation and Die-Away Kinetics-Development of the Core Facility at the University of Rochester
Investigators: Frances Eun-Hyung Lee, MD, Marc Hellerstein, PhD, Hulin Wu, PhD, Ignacio Sanz,MD, Tim Mosmann, PhD
Dates: May 1st, 2007- April 30th, 2008
Brief Description of Project: This project will establish a "human in vivo labeling" core facility at SMD that will be accessed by investigators in a diversity of disciplines such as Cancer biology, Microbiology, Immunology, Medicine, and Biodefense. Heavy water (2H20) or glucose (2H-glucose) labeling of DNA is the only safe and direct human measure of cell kinetics in vivo. Kinetics of rare immune populations has been difficult to study, however, due to extremely low frequencies. In this proposal, protocols will be developed for in vivo labeling, focusing particularly on techniques for studying extremely low frequency immune cell populations (approximately 50,000-100,000 cells). As an initial example, the immune kinetics of VH4-34 B cells, a marker of B cell tolerance, will be measured in vivo in patients with Systemic Lupus Erythematosis (SLE) and in healthy control subjects. This study will be the first to measure in vivo proliferation and die-away rates of these low frequency immune cells as a biomarker of autoimmune disease. This core facility will be instrumental in securing future NIH funding for many UR investigators.
In addition to funding internal grant awards for the development of novel methodologies, other goals of this component of the CTSI are to facilitate interactions regarding new methodologies among researchers, and to assess research needs of CTSI faculty and address them.
I trust you will agree—due to the formative efforts of Drs. Treanor and Schwarz, and the creative response of our faculty, we are off to a great start.
Meliora,
David S. Guzick, MD, PhD
Dean, School of Medicine and Dentistry
