Select a year 1998 1999 2000 2001 2002    Select a researcher Bruce N. Ames, Ph.D. Giuseppe Attardi, M.D. Steven N. Austad, Ph.D. Tamas Bartfai, Ph. D. Nir Barzilai, M.D. Seymour Benzer, Ph.D. Seymour Benzer, Ph.D. Helen M. Blau, Ph.D. Roger Brent, Ph. D. Linda B. Buck, Ph. D. Jochen Buck, M.D., Ph.D. Judith Campisi, Ph.D. Luca Cavalli-Sforza, M.D. Catherine F. Clarke, Ph.D., co-PI James E. Cleaver, Ph.D. Stanley N. Cohen, M.D. Gretchen J. Darlington, Ph.D. Titia de Lange, M.D. , Ph.D. Stephen J. Elledge, Ph.D. Art Gafni, Ph.D. Lawrence S.B. Goldstein, Ph.D. Daniel E. Gottschling, Ph.D. Michael E. Greenberg, Ph.D. Paul Greengard, Ph.D. Carol W. Greider, Ph.D. Jack D. Griffith, Ph. D. Leonard Guarente, Ph.D. Philip C. Hanawalt, Ph. D. Stephen Helfand, M.D. Peter J. Hornsby, Ph. D. Thomas E. Johnson, Ph.D. Cynthia J. Kenyon, Ph.D. Cynthia J. Kenyon, Ph.D. Stuart Kim, Ph.D. Thomas Kornberg, Ph. D. Pamela L. Larsen, Ph.D., co-PI Charles M. Lieber, Ph. D. Stuart Lipton, M.D., Ph.D. Gordon Lithgow, Ph.D. Lawrence A. Loeb, M.D., Ph.D. Victoria Lundblad, Ph.D. Mark Mayford, Ph.D. Simon Melov, Ph.D. James F. Nelson, Ph.D. Fernando Nottebohm, Ph.D. Thomas Perls, M.D., M.P.H Gregory A. Petsko, D. Phil. Daniel Promislow, Ph.D. David Ron, Ph. D. Gary Ruvkun, Ph.D. Thomas P. Sakmar, M.D. Jerry W Shay, Ph.D. Sangram S. Sisodia, Ph. D. Rudolph E. Tanzi, Ph.D. David S. Thaler, Ph.D. John Tower, Ph.D. Douglas C. Wallace, Ph.D. Sherman M. Weissman, M.D. Phyllis M. Wise, Ph.D. Woodring E. Wright, M.D., Ph.D. Select a project Translating Yeast Telomere Biology to Human Cells: Identi...A High Throughput Screen for Longevity GenesAging in Mutator and Antimutator MiceAging-dependent Large Accumulation of Mutations at Specifi...Analysis of genes that control aging in C. elegansBicarbonate-activated adenylyl cyclase and agingBone Marrow to Brain: Searching for markers of bone marrow...Can the Heat-Shock Response Extend the Lifespan of the Mou...Cell Transplantation Models for Gene Action in Human AgingChronic Neuroprotection during Aging by UCP Mediated Simul...Connections Between the Telomere Sensing and DNA Damage Ac...Critically Testing the Free Radical Theory of Aging, and D...Endogenous DNA Damage and Mechanisms of AgingEstradiol is a Neuroprotective Factor in the Aging Brain: ...Exploration of the C.elegans insulin-like aging pathwayExploring the genetics of extreme longevityFunctional Tests of Replicative Aging in Organotypic Skin ...Gene-gene interactions, gene networks and aging in natural...Genes Controlling Longevity in CentenariansGenetic Dissection of Aging in DrosophilaGenetic Mechanisms of Exceptional Oxidative Damage Resista...Genetic Mechanisms Regulating Replicative Aging in Diffier...Genomic approaches to studying aging in C. elegansHow cells die in Alzheimer's and other neurodegenerati...Hypothesis to be tested: some aspects of functional aging ...Identification of Candidate Genes for Longevity in Long Li...Identification of gerontogenes in the mouseIdentification of Longevity Genes in Founder PopulationsIdentification of Protein Regulators of Self-renewal, Diff...Intersection of two pathways in control of aging: nutritio...Life extension genes in DrosophilaMitochondrial Aging in the ChimpanzeeMitochondrial Mutation and AgingMitochondrial swirls, a link between oxidative stress and ...Molecular analysis of mammalian agingMolecular Determinants of Hippocampal Neuroplasticity in a...Molecular through Cellular Changes Responsible for Alzheim...Mutagenic Screen for Longevity Genes in MiceNovel APP - containing synaptic organelles and Alzheimer&#...Probing the role of axonal transport disturbance and trans...Proteotoxicity and AgingRapid Screening for Longevity Mutants in MiceRepair of Oxidative DNA Damage in Human NeuronsReplicative senescence in S. cerevisiaReplicative Senescence of Drosophila Stem Cells in VivoReversal of Mitochondrial Decay: From Rats to HumansRole of telomeres and telomerase in human agingRole of the multiligand receptor, LRP. In Alzheimer’s dise...Single Molecule Studies of Age-Related Alterations in Heat...Telomere Looping and Control of Cell AgingTelomeres, Cell Phenotype and AgingThe Chromophore Regeneration Pathway in Age-related Macula...The Molecular/Physiological Basis for Accelerated Aging in...The Rapid Identification of Hormones and Pharmacological C...The Role of P13K/Akt Dependent Phosphorylation of a Mammal...The Role of T-loops in Aging of Human CellsThe Roles of Recombination and Telomerase in Telomere Main...Toward a Comprehensive Assessment of Gene Expression durin...Use of Blood Stem Cells to Regenerate Neurons via the Tran... Select an institution Albert Einstein College of Medicine of Yeshiva University Baylor College of Medicine Boston Medical Center Brandeis University Buck Institute for Age Research Burnham Institute California Institute of Technology Children's Hospital, Boston Children's Hospital, Oakland Research Institute Fred Hutchinson Cancer Research Center Harvard Medical School Johns Hopkins University School of Medicine Lawrence Berkeley National Laboratory Massachusetts General Hospital Massachusetts Institute of Technology Molecular Sciences Institute Rockefeller University Scripps Research Institute Skirball Institute - New York University School of Medicine Stanford University Medical Center Stanford University School of Medicine University of California - Davis University of California - Irvine University of California - Los Angeles University of California - San Diego, Howard Hughes Medical Institute University of California - San Francisco University of California - San Francisco, UCSF Cancer Center University of Chicago University of Colorado - Boulder University of Connecticut Health Center University of Georgia University of Idaho University of Michigan University of North Carolina - Chapel Hill University of Southern California University of Texas Health Science Center - San Antonio University of Texas Southwest Medical Center University of Texas Southwestern Medical Center University of Washington Weill Medical College of Cornell University Yale University School of Medicine

Tamas Bartfai, Ph. D. Scripps Research Institute

Aging increases the vulnerability of the nervous system to damage by free radicals and by glutamate-mediated excitotoxicity following ischemia and reperfusion. Ischemia-reperfusion injuries, transient ischemic attacks and ischemic stroke are more common above 60 than with younger men and women.

The increased vulnerability of the nervous system is expressed by an increased number of neuronal cells undergoing free radical and/or glutamate caused necrotic and apoptotic cell death. The loss of those central nervous system neurons is manifested by neurological motor and cognitive deficits; which increase with aging.

Vulnerability of mitochondria during ischemia and its role in cell death are now being appreciated. The mitochondrial Uncoupling Proteins UCPs are integral membrane proteins which can dissipate the proton gradient across the mitochondrial innermemebrane and act to coordinate respiration and ATP synthesis and free radical formation and thus balance risks of oxygen toxicity and energy (ATP) need of the cell. UCP activity may play a key role in the mitochondrial stress response and defense and hence our focus on UCP activation.

UCP is upregulated in several neuronal and cellular toxicity models, and we believe that its upregulation, at least initially, is part of the stress response aimed at protecting the mitochondria and thereby the whole neuron from excitotoxicity. The roles of UCP in reducing free radical formation have been known. In vitro data on liver, heart and brain mitochondria clearly shows that uncoupling respiration from ATP synthesis by pharmacological means (DNP) or by activation of UCP reduces free radical formation at Complex I and III of the respiratory chain. Uncoupling also partially depolarizes the mitochondria so it is NOT able to take up as much Ca²+ as it would if its membrane potential were intact. Partially uncoupled mitochondria were shown to survive excitotoxic glutamate mediated Ca²+ influx without opening the mitochondrial transition pore and without committing the cell towards an apoptotic program via cytochrome C release.

The proposal is centered on achieving a proof principle for UCP activation as a acute and chronic neuroprotective measure in aging by using 3 transgenic mouse strains that overexpress in brain mitochondria UCP2: 1.) in all forebrain neurons under the PDGFb promoter, 2.) specifically in catecholaminergic neurons under tyrosine hydroxylase promoter and 3.) only in the hypothalamus under hypocretin promoter. We propose this transgenic approach since we do not have any CNS-specific and CNS penetrant activator of UCP to test this hypothesis pharmacologically today. By studying the neuronal damage, in UCP overexpressing and wild type mice, caused by ischemia (focal and global) and by MPTP, that via free radical mechanisms kills dopaminergic neurons, we will be able to conclude if increased UCP activity is neuroprotective in vivo and if the combination of protection from both free radical and excitotoxic is indeed producing robust synergistic neuroprotection as expected theoretically.

Contact Dr. Bartfai.