Physiology

STEVEN ESTUS, Ph.D. Associate Professor Director of Graduate Studies, IBS Program Ph.D. Case Western Reserve University, 1989 Office: SB-332, Sanders Brown Center on Aging 0230 Tel: (859) 257-1412 ext. 264 Lab SB-332 Tel: 257-1412 ext. 262 E-mail: steve.estus@uky.edu

In our laboratory, we seek to elucidate the molecular and cellular mechanisms underlying neurodegenerative disease. Over the past several years, the focus of our laboratory has shifted from neuronal death mechanisms per se to the use of molecular genetics to identify genetic variants, or polymorphisms, that alter gene expression or function and thereby increase the risk of Alzheimers disease (AD). Since cholesterol is emerging as a possible AD modulator, we are currently evaluating polymorphisms in genes that encode proteins critical to cholesterol homeostasis, particularly those encoding apoE receptors. As we identify these polymorphisms, we are expressing the genes in cells in vitro to evaluate their function, and evaluating mice deficient for these genes for issues relevant to AD, e.g., amyloid-beta levels.

Overall, our work is facilitated by our association with the Sanders-Brown Center on Aging and its Alzheimers Disease Center (ADC). Our ADC has been critical in providing hundreds of DNA samples from well-characterized AD and control individuals, which are necessary for genotyping polymorphisms, as well as autopsy-derived CSF and brain samples, which has allowed us to quantify the levels of the gene products and genetic variant proteins of interest in a rapid and human-disease relevant fashion.

In summary, the overall goal of our laboratory is to use human genetics to investigate hypotheses evaluating pathways critical to AD risk and progression. These studies contribute to the fight against AD by identifying individuals at risk, identifying possible novel therapies, and tailoring therapy to responsive individuals.

Current Funding:

2006-2010 NIH NIH R01 AG AG026147. "LDLR genetics, splicing and AD risk." S.Estus, PI. $767,520 total direct costs.

Recent publications:

F. Zou, R.K. Gopalraj, J. Lok, H. Zhu, I-F. Ling, J. F. Simpso, H. M. Tucker, J. F. Kelly, S. G. Younkin, D. W. Dickson, R. C. . Petersen, N.R. Graff-Radford, D. A. Bennett, J. E. Crook, S. G. Younkin, S. Estus. Sex-dependent Association of a Common Low Density Lipoprotein Receptor Polymorphism with RNA Splicing Efficiency in the Brain and Alzheimers Disease. Hum Mol Genet. Epub ahead of print. (2007)

H. Zhu, H.M. Tucker, K. Grear, J. F. Simpson, A. K. Manning, L. A. Cupples and S. Estus. A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol. Hum. Molec. Genet. 16: 1765-1772 (2007).

J. Tangpong, M.P. Cole, R. Sultana, S. Estus, M. Vore, W. St. Clair , S. Ratanachaiyavong, D.K. St. Clair, and D.A. Butterfield, Adriamycin Mediated Nitration of Manganese Superoxide Dismutase in the Central Nervous System: Insight into the Mechanism of Chemobrain. J. Neurochem. 100:191-201 (2007).

H. Zhu, R. K.Gopalra, J. F. Kelly, D. A. Bennett and S. Estus. Lack of genetic association of cholesteryl ester transfer protein polymorphisms with late onset Alzheimers disease. Neurosci. Lett. 381:36-41 (2005).

N Ertekin-Taner, J. Ronald. L. Feuk, J. Prince, M. Tucker, L. Younkin, M. Hella, S. Jain, A. Hackett, L. Scanlin, J. Kelly, M. Kihiko-Ehman, M. Neltner, L. Hersh, M. Kindy, W. Markesbery, M. Hutton, M. de Andrade, R.C. Petersen, N. Graff-Radford, S. Estus, A.J. Brookes, S.G. Younkin. Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene. Hum. Mol. Genet. 14: 447-460 (2005).

Other Publications