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Research Assistant Professor of Biochemistry and Biophysics
Ph.D. University of Rochester (1987)
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NMR imaging and spectroscopy; Tumor biology; RNA structure determination; anion transport
The lab is involved with a wide variety of collaborations with investigators from throughout the Medical Center and River Campus. Ongoing projects include NMR structural studies of model and native RNA, methods for rapid acquisition of restraints to aid secondary structure prediction of large RNA molecules, MRI studies of tumor vascular physiology and response of tumors to therapy, and development of MRI methods for efficient histological analysis and for brain functional studies of the auditory system. While the diverse range of projects encompass applications in oncology, molecular biophysics, radiology, and neuroscience, they all employ magnetic resonance spectroscopy and/or imaging as an experimental tool.
Structural studies of model and native RNA internal loops are combined with thermodynamic data to better understand the forces directing nucleic acid chemistry, with particular emphasis on RNA folding. Studies of the properties of short oligonucleotides provide insight into the interactions determining the sequence dependence of the structures, energetics, and dynamics of nucleic acids. Results from these studies are used to improve algorithms for predicting secondary structures of naturally occurring RNA. NMR methods are also being developed to provide restraints, similar to chemical mapping, which can help identify the correct structure from a field of energetically favorable structures. These NMR studies are carried out with the lab of Doug Turner.
The development and optimization of cancer therapies is aided by monitoring critical aspects of tumor physiology. All tumor therapies must deal with the fact that major portions of many tumors are difficult to treat because of poor blood supply, low oxygen concentrations, and uniquely adapted cellular metabolisms. Many therapies directly target the vasculature. We have been exploring methods and agents to monitor tumor vascular properties, particularly dynamic contrast-enhanced MRI (DCE-MRI) which is being tested in clinical trials as a therapy response bio-marker. The aim is to develop tools which can aid identification of events following (or during) a treatment protocol, and allow treatment (or pretreatment) conditions to be rationally optimized. These DCE-MRI studies are carried out with the lab of Bruce Fenton.
MRI microscopy in mouse models is being used to characterize benign prostatic hypertrophy and other lower urinary tract symptoms (LUTS), and pelvic organ prolapse. The aim is to identify 1) tissue sites causing LUTS in animals treated with testosterone + estradiol or bisphenol-A with particular focus on peri-urethral glandular epithelial proliferation, 2) sites of obstruction in a prostatic tumor model, or 3) the development and properties of pelvic organ prolapse in a colony of mice with spontaneous presentation. High-resolution imaging of the lower abdomen of whole animals, sectioned tissue, or excised urethras is performed in fixative containing contrast agent. These MRI microscopy studies are carried out with the labs of Ronald Wood, Jay Reeder, and William Ricke.
Manganese-enhanced functional MRI (MEMRI) identifies activated regions because manganese, which is co-accumulated with calcium, is paramagnetic and enhances T1-weighted images. We have used MEMRI to identify tonotopic laminae in the mouse auditory system. Early childhood sensorineural hearing (SNHL) loss affects 3 in 1000 in the US. The DBA/2J mouse strain provides a model for studies of this early hearing loss. Exposure to an enriched auditory environment increases auditory sensation levels and improves central auditory temporal processing in these mice. Preliminary data suggests that we will be able to use MEMRI in the DBA mouse model to identify regions of the auditory midbrain in which auditory processing has been restored. With the combination of in vivo functional imaging and electrophysiology data recorded from the same animal, we will evaluate global reorganization and local unit changes following exposure to the enriched auditory environment. By understanding brain plasticity occuring following this early intervention, the hope is to bring this treatment to the clinic, as a bridge to permanent treatment of childhood SNHL. In another project, causes of the difficulty of hearing in background noise experienced by many elderly listeners is being investigated. Little is know about the underlying age-related neural coding deficits or the brain circuits involved. It is known that inhibitory neurochemistry in many different key central auditory brain regions declines with age and there is a reported age-related decline of over 30% in both GABAA and GABAB immunoreactive neurons in auditory cortex of aged rats. Using MEMRI young and old mice will be exposed to a complex spectrotemporal stimuli and map age-related changes associated with deficits in neural processing. The MEMRI studies are carried out with the lab of Joe Walton.
By monitoring the metabolism of hearts that are stored at low temperatures, we have demonstrated how access to oxygen plays a critical role in the eventual viability of the transplanted organ. An organ stored at freezing temperatures consumes far less oxygen than the same organ at room or body temperature. Thus, oxygen can diffuse much farther into the tissue and help maintain normal levels of important metabolites. By continuously mapping the metabolic status in the cold-stored heart, we can assess the effectiveness of different approaches to maintaining tissue oxygen.
In a clearly related process, but entirely different field, we have been studying the physiology of freeze tolerant vertebrates (specifically, wood frogs) under conditions which mimic a winter freeze. The goal is to better understand the adaptations which allow these animals to survive prolonged periods during which 60%-70% of their body fluid is turned to ice.
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McNanley AR, Johnson AM, Flynn MK, Wood RW, Kennedy SD, Reeder JE (2009) Inherited pelvic organ prolapse in the mouse: preliminary evaluation of a new murine model. Int Urogynecol J Pelvic Floor Dysfunct, 20:19-25
Hart JM, Kennedy SD, Mathews DH, Turner DH (2008) NMR-assisted prediction of RNA secondary structure: identification of a probable pseudoknot in the coding region of an R2 retrotransposon. J Am Chem Soc, 130:10233-9
Shankar N, Xia T, Kennedy SD, Krugh TR, Mathews DH, Turner DH (2007) NMR reveals the absence of hydrogen bonding in adjacent UU and AG mismatches in an isolated internal loop from ribosomal RNA. Biochemistry, 46:12665-78
Chen G, Kierzek R, Yildirim I, Krugh TR, Turner DH, Kennedy SD (2007) Stacking Effects on Local Structure in RNA: Changes in the Structure of Tandem GA Pairs when Flanking GC Pairs are Replaced by isoG-isoC Pairs. J Phys Chem B, 111:6718-6727
Tolbert BS, Kennedy SD, Schroeder SJ, Krugh TR, Turner DH (2007) NMR structures of (rGCUGAGGCU)2 and (rGCGGAUGCU)2: probing the structural features that shape the thermodynamic stability of GA pairs. Biochemistry, 46:1511-22
Gu T, Kennedy SD, Chen Z, Schneider KA, Zhong J (2007) Functional MRI at 3T using intermolecular double-quantum coherence (iDQC) with spin-echo (SE) acquisitions. Magma, 20:255-64
Wong CK, Kennedy SD, Kwok E, Zhong J (2007) Theoretical studies of the effect of the dipolar field in multiple spin-echo sequences with refocusing pulses of finite duration. J Magn Reson, 185:247-58
Shankar N, Kennedy SD, Chen G, Krugh TR, Turner DH (2006) The NMR structure of an internal loop from 23S ribosomal RNA differs from its structure in crystals of 50s ribosomal subunits. Biochemistry, 45:11776-89
Chen G, Kennedy SD, Qiao J, Krugh TR, Turner DH (2006) An alternating sheared AA pair and elements of stability for a single sheared purine-purine pair flanked by sheared GA pairs in RNA. Biochemistry, 45:6889-903
Zheng B, Chen Z, Kennedy SD, Zhong J (2006) iDQC MRI weighted by longitudinal relaxation in the rotating frame. Magn Reson Med, 56:327-33
Chen G, Znosko BM, Kennedy SD, Krugh TR, Turner DH (2005) Solution structure of an RNA internal loop with three consecutive sheared GA pairs. Biochemistry, 44:2845-56
Kennedy SD, Zhong J (2004) Diffusion measurements free of motion artifacts using intermolecular dipole-dipole interactions. Magn Reson Med, 52:1-6
Zhong J, Chen Z, Kennedy SD (2004) Properties and applications of intermolecular dipole-dipole interactions in biomedical NMR. Review invited by Recent Research Developments in Chemical Physics, 5:23-55
Schroeder SJ, Fountain MA, Kennedy SD, Lukavsky PJ, Puglisi JD, Krugh TR, Turner DH (2003) Thermodynamic stability and structural features of the J4/5 loop in a Pneumocystis carinii group I intron. Biochemistry, 42:14184-96
Yan S, Kennedy SD, Koide S (2002) Thermodynamic and kinetic exploration of the energy landscape of Borrelia burgdorferi OspA by native-state hydrogen exchange. J Mol Biol, 323:363-75
Zhong J, Chen Z, Kwok WE, Kennedy SD, You Z (2002) Optimization of blood oxygen level-dependent sensitivity in magnetic resonance imaging using intermolecular double-quantum coherence. J Magn Reson Imaging, 16:733-40
Layne JrJR,Kennedy SD (2002) Cellular energetics of frozen wood frogs (Rana sylvatica) revealed via NMR spectroscopy. J. Thermal Biology, 27:167-173
Zhong J, Chen Z, Kwok WE, Kennedy SD (2001) Enhanced sensitivity to molecular diffusion with intermolecular double-quantum coherences: implications and potential applications. Magn. Reson. Imag., 19:33-39
Chen Z, Kennedy SD, Zhong J (2000) Quantitation of intermolecular dipolar effects in NMR spectroscopy and high order MSE MR imaging. Magma, 11:122-8
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E-Mail: Scott_Kennedy@urmc.rochester.edu
Scott Kennedy
Department of Biochemistry and Biophysics
University of Rochester School of Medicine and Dentistry
601 Elmwood Ave, Box 712
Rochester, New York 14642
Office: Medical Center Annex B-124
Telephone: (585) 275-7585; Fax: (585) 275-6007
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