| TH E N I H C A T A L Y S T | S E P T E M B E R – O C T O B E R 2008 |
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Peter R. Rapp received his Ph.D. from the University of North Carolina at Chapel Hill in 1986 and conducted postdoctoral training at the Salk Institute for Biological Studies in La Jolla, Calif., where he was later promoted to Staff Scientist. He subsequently held faculty positions in the Center for Behavioral Neuroscience at the State University of New York, Stony Brook (1993-1997), and the Departments of Neuroscience, and Geriatrics and Adult Development, and the Kastor Neurobiology of Aging Laboratories at the Mount Sinai School of Medicine in New York (1997-2008). At Mount Sinai he served as Interim Chair of the Department of Neuroscience (2006-2008) and Co-Director of the Graduate Training Program in Neuroscience. Rapp joined NIH in July 2008 as Senior Investigator and Chief of NIA's Laboratory of Experimental Gerontology and head of the Neurocognitive Aging Section.
Research in the Neurocognitive Aging Section (NAS) aims to understand the mechanisms of normal cognitive aging as a basis for developing effective therapeutic interventions. Our early studies in nonhuman primates succeeded in establishing a basic neuropsychological profile of aging, and we have now turned attention to the specific nature of decline, with the aim of defining effects on the component processes of declarative/episodic memory. An important goal is to test the working hypothesis that age-related decline results from large-scale restructuring of the neural networks that support normal memory. Toward this end, young and aged monkeys receive periodic high-resolution, structural MRI and corresponding fluorodeoxyglucose PET scans over the course of neuropsychological testing. Metabolic activity in the prefrontal cortex and medial temporal lobe system is then evaluated in relation to individual variability in the cognitive outcome of aging. The incidence of menstruation and urinary hormone profiles are also tracked, enabling analysis of the behavioral and imaging results in the context of naturally occurring ovarian failure.
Other collaborative studies in nonhuman primates take advantage of the uniquely valuable translational potential of this animal model. Although available evidence indicates that aging modulates the cognitive and neurobiological effects of ovarian hormone manipulation, this proposal has proved difficult to test in women. Studies currently underway in monkeys are therefore designed to compare the cognitive effects of multiple hormone replacement strategies, modeled on regimens available for clinical use in women. These investigations establish a unique framework of behavioral data for related collaborative initiatives focusing on the neurobiological effects of ovarian hormone manipulation.
Age-associated cognitive decline in humans prominently involves disrupted interactions between multiple memory-related brain systems. Ongoing studies in my lab are among the first to explore this issue in an aged rat model, using a plus-maze procedure and quantitative in situ hybridization for plasticity-related gene Arc to test the possibility that deficits in cognitive flexibility are coupled with functional network reorganization across the prefrontal cortex, dorsal striatum and hippocampus.
Current perspectives implicate alterations in plasticity mechanisms as a basis for cognitive aging. Related evidence indicates that promoting chromatin rearrangement permissive for gene transcription by pharmacological means enhances hippocampal long-term potentiation and benefits memory. These results predict that treatments targeting epigenetic transcriptional control may improve the neurocognitive outcome of aging. My lab is testing this proposal in both rats and nonhuman primates, coordinating behavioral assessment with the analysis of relevant molecular signatures of successful aging. Other studies are examining the resting basal status of epigenetic transcriptional control and the dynamic regulation of these mechanisms under learning activated conditions.
Progress in research on neurocognitive aging is critically supported by advances in understanding the fundamental structure and organization of memory in brain. Based on this perspective, and guided by the consensus that the medial temporal lobe system is critical for normal episodic memory, an additional line of investigation in my lab aims to identify the information-processing functions of the primate hippocampus that mediate this capacity. In these studies, subjects are tested across a battery of both standard and novel tasks, manipulating demands on candidate properties of episodic memory: 1) the temporal organization of memory, 2) memory for spatial and nonspatial context, 3) "autobiographical" memory, and 4) the relational organization of memory. Taken together, these investigations are expected to substantially advance our understanding of the structure and organization of medial temporal lobe memory in primates and, ultimately, fuel research on a variety of conditions in which memory is prominently affected.
Javed Khan obtained his bachelor's degree in 1984 and his master's degrees in 1989 in immunology and parasitology at University of Cambridge, England. He subsequently obtained his M.D. there and the postgraduate degree of MRCP (Membership of the Royal College of Physicians), equivalent to board certification in the United States. After clinical training in internal medicine and pediatrics as well as other specialties, he received a Leukemia Research Fellowship. In May 2001, Khan joined the NCI Pediatric Branch as a tenure-track investigator and became tenured in April 2008.
The overall mission of my research is to leverage the power of genome-wide high-throughput "omic" approaches to improve the outcome of patients with high-risk cancers, with a focus on neuroblastoma, the most common solid extra-cranial tumor of childhood. My research program has four primary goals:
My lab has applied DNA microarray techniques, artificial neural networks and other computational algorithms to identify gene-expression profiles that can diagnose the small, blue, round cell tumors of childhood as well as predict outcome in patients with neuroblastoma. Using DNA copy number changes detected by Comparative Genomic Hybridization, we have modeled how these neuroblastoma tumors progress and have provided the first proof that they do not progress from low-stage to high-stage tumors. We have molecularly characterized a large panel of pediatric xenografts that are currently used to screen new drugs for treating these malignancies. We are investigating the role of miRNAs in the development and progression of pediatric cancers, and we have mapped miRNA mir-34a to 1p36, a region frequently deleted in MYCN-amplified neuroblastoma and which controls the expression level of MYCN itself. We are spearheading the use of next-generation whole-genome sequencers to perform mutational analysis, methylation and mRNA and miRNA profiling of pediatric solid tumors.
Recently my research team was awarded a grant from the Therapeutically Applicable Research to Generate Effective Treatments (NBL-TARGET) Initiative to identify targets for neuroblastoma. This is a collaboration among the NCI, Children's Hospital of Philadelphia, Children's Hospital Los Angeles and the Children's Oncology Group. We also recently have launched the NanoBioSensor Initiative to develop devices for the detection of nucleic acid hybridization using carbon nanotube and silicon nanowire transistors for diagnostic purposes. This is a collaboration among the NCI, University of Maryland and NASA.