|Senior Scholar Program|
|1998 Senior Scholar Awardees|
Animals with longer lifespan usually have higher resistance to stress. The extended-lifespan Drosophila mutant methuselah resists all three different stresses tested, heat, starvation, and paraquat, an oxygen free radical generator. This suggests a molecular approach to identifying genes which are up-regulated by all three stresses, as candidates for longevity genes. The approach is to employ cDNA subtraction technique, using flies separately exposed to each of the stresses, and subtracting, by hybridization, the cDNA from unstressed flies, and to look for stress up-regulated genes. The converse subtraction would enrich for down-regulated genes. To find genes that are up regulated by all three stresses, a stressed-minus-unstressed cDNA library was used to produce duplicate microarrays. These were separately hybridized with each of the other two kinds of stress-minus-unstressed cDNA probes. Clones showing positive results with both of the cDNA probes are candidates for genes that are up-regulated by all three different stresses. The positive clones are then to be checked by Northern blotting, to confirm whether they are up-regulated in flies subjected to the various stresses. The corresponding genes will be used to make transgenic flies to be tested for stress resistance and lifespan.
Judith Campisi, Ph.D.
Telomere shortening appears to be a significant factor in cellular aging in tissue culture. Dr. Campisi proposes to systematically search for proteins that associate with human telomeres and to characterize their effects on replicative life-span in order to determime whether any of these proteins are involved in cellular senescence changes.
Luca Cavalli-Sforza, M.D.
Dr Cavalli-Sforza will search the DNA of centenarians from around the world in order to identify the genes which are responsible for very long life, using cell lines developed from tissue sample taken from centenarians and from younger controls.
Stephen J. Elledge, Ph.D.
Daniel E. Gottschling, Ph.D.
Dr. Gottschling's studies in the yeast S. cerevisia will test the hypothesis that there are numerous pathways by which cells come to the end of their replicative lifespan. He will eliminate potential pathways (e.g. telomere shortening or rDNA circles) one at a time, or in combination in order to elicit additional pathways to senescence.
Paul Greengard, Ph.D.
Amyloid Precursor Protein (APP) is the precursor of Aď˘, which appears to be critical in the initiation of Alzheimer's disease. Dr. Greengard's research will characterize synaptic organelles that are the major site of APP in nerve terminals.
Carol W. Greider, Ph.D.
Telomerase is the predominant mechanism that allows telomere length maintenance in eukaryotic cells. Telomerase activity is up-regulated in over 90% of human tumors suggesting that this enzyme is necessary for tumor cell growth. Evidence from human and mouse cells suggests that telomerase inhibition will lead to cell death and may be a useful approach to cancer chemotherapy. However, work in yeast has shown that when telomerase activity is eliminated, recombination mediated pathways for telomere maintenance can still allow cell survival. Over the past five years evidence has accumulated that such recombination-based pathways also may function in human and mouse cells where telomerase is absent. Thus, if telomerase inhibition is to be seriously considered as a therapeutic approach to cancer treatment, it is essential to determine whether these bypass mechanisms will allow the continued growth of tumors and selection for telomerase inhibitor resistant cells in vivo. To test whether recombination will play a role in the growth of tumor cells in the absence of telomerase, we are crossing the telomerase null mouse to several recombination deficient animals. mTR-/- mice, that lack the RNA component of telomerase, are viable for 6 generations, and show progressive telomere shortening. After five to six generations, telomere shortening severely compromises the ability of many cell types to survive. However, once transformed, these telomerase null cells can still form tumors in vivo. We will determine whether a deficiency in recombination will reduce the ability of these cells to form tumors in the absence of telomerase. These studies will allow a more complete understanding of the role of both recombination and telomerase in telomere maintenance and may lead to more sophisticated approaches to telomerase inhibition therapies.
Leonard Guarente, Ph.D.
Dr. Guarente is extending his studies of genetic mechanisms of aging in yeast to mammals. He intends to determine changes in rDNA that accumulate with age in mice. He will then generate transgenic mice with specific rDNA changes in order to test whether specific changes cause aging.
Thomas E. Johnson, Ph.D.
In previous research, Dr. Johnson identified gerontogenes (genes that specify length of life) in the nematode worm C. elegans. Dr. Johnson now proposes to search for such genes in mice using Recombinant Inbred line and by stress induced mutagenisis.
Cynthia J. Kenyon, Ph.D.
Dr. Kenyon believes that the study of short-lived mutants of C. elegans may lead to the identification of important life-span regulating genes. She proposes to identify such genes. She will also import human genes into C. elegans short-lived mutants in order to see which of theses genes best compensate for the lost worm gene.
Louis M. Kunkel, Ph.D.
Dr. Kunkel intends to analyze three human families with clusters of extremely long-lived individuals in order to identify specific genes responsible for extreme longevity.
Gregory A. Petsko, D. Phil.
Fragments of Alzheimers polypeptide (APP) are found in senile plaques. Some fragments ( Ab 1-40 and 1-42 ) appear to be toxic to the brain. Dr. Petsko proposes to identify the enzyme (s) that produce these fragments and then, using Ab resistant mutants, determine how the Ab peptides kill nerves.
Gary Ruvkin, Ph.D.
Dr. Ruvkin has previously shown that an insulin-like signaling pathway regulates longevity and metabolism in C. elegans. The most important output of this pathway in C. elegans is the transcription factor DAF-16. Dr. Ruvkin now proposes to search for the downstream targets of DAF-16 in order to identify the downstream daf-16 genes involved in longevity control.
Jerry W. Shay, Ph.D.
Telomere length appears to be critically involved in cellular senescence and in cellular immortality. Telomerase shortening results in cellular senescence, while stabilization of telomere length results in cellular immortality and cancer. Regulation of telomere length is usually, but not always, maintained by levels of the enzyme telomerase. Dr. Shay proposes to clarify alternative mechanisms to maintain telomeres, determine the mechanism by which shortening of telomeres induces cellular senescence, and investigate the genetic mechanism underlying the premature aging syndrome, Hutchinson-Gilford progeria.
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Richard L. Sprott, Ph. D.