Steven Estus, PhD
Connect
859-218-3858steve.estus@uky.edu
Positions
- Professor, Department of Physiology
College Unit(s)
Research
In our laboratory, we seek to elucidate the mechanisms underlying the actions of genetic polymorphisms that modulate the risk of disease, especially Alzheimer’s disease (AD). Our goal is to translate these findings into novel approaches to prevent or treat human disease. We are primarily focused on AD genetics because genetic risk factors drive the majority of AD risk. Also, since genetic variants modulate AD risk, then by definition, drugs that act similarly will also modulate AD risk. Hence, we interpret the pathways identified by genetics as validated drug targets. Our experimental approach begins by noting that high throughput genome wide association studies have identified a series of single nucleotide polymorphisms (SNP)s that are robustly associated with AD risk. Hence our goal is to perform molecular genetic studies to identify the mechanisms of action underlying these SNPs. The primary actions of these SNPs, or their co-inherited proxy SNPs, are to (i) alter amino acid sequence, (ii) alter gene expression or (iii) alter mRNA splicing. For each of the AD-associated SNPs, we are working through the process of determining the molecular impact of the SNP. For example, a CD33 SNP has been associated with AD risk. We found that this SNP acts through a co-inherited proxy SNP to modulate the splicing efficiency of the second exon in CD33. The allele that protects from AD risk reduces the inclusion of exon 2. The CD33 isoform lacking exon 2 is predicted to produce a non-functional CD33. Hence, our findings suggest that reducing CD33 function protects from AD risk. We are currently pursuing this hypothesis at multiple levels, including the study of CD33 inhibitors. In other work, we are evaluating AD-associated SNPs in INPP5D, ABI3 and FCER1G. Overall, our work is facilitated by our association with the Sanders-Brown Center on Aging and its Alzheimer's 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 identify molecular mechanisms that modulate the risk of human disease, especially AD. These studies contribute to the fight against AD by identifying individuals at risk, identifying possible novel therapies, and tailoring therapy to responsive individuals.
Selected Publications
Malik M, Simpson JF, Parikh I, Wilfred BR, Fardo, DW, Nelson PT, and Estus S. CD33 Alzheimer’s risk-altering polymorphism, CD33 expression and exon 2 splicing. J. Neurosci. 33: 13320-05 (2013). PMC3742922
Vasquez JB, Fardo, DW and Estus, S. ABCA7 expression is associated with Alzheimer’s disease polymorphism and disease status. Neurosci. Lett. 556: 58-62 (2013) PMC3863933
Parikh I, Fardo DW, Estus S. Genetics of PICALM Expression and Alzheimer's Disease. PLoS One. 9(3):e91242 (2014). PMC3949918
Parikh I, Medway C, Younkin S, Fardo DW, Estus S. An intronic PICALM polymorphism, rs588076, is associated with allelic expression of a PICALM isoform. Mol Neurodegener. 9(1):32 (2014). PMC4150683
Malik M, Chiles J 3rd, Xi HS, Medway C, Simpson J, Potluri S, Howard D, Liang Y, Paumi CM, Mukherjee S, Crane P, Younkin S, Fardo DW, Estus S. Genetics of CD33 in Alzheimer's Disease and Acute Myeloid Leukemia Hum Mol Genet. 24: 3557-3570 (2015). PMC4498153
Malik M, Parikh I, Vasquez JB, Smith C, Tai L, Bu G, LaDu MJ, Fardo DW, Rebeck GW, Estus S. Genetics ignite focus on microglial inflammation in Alzheimer's disease. Mol Neurodegener. 10:52 (2015). PMC4595327
Vasquez JB, Simpson JF, Harpole R, Estus S. Alzheimer's Disease Genetics and ABCA7 Splicing. J Alzheimer’s Dis. 59:633-641 (2017) PMC28655137.
Estus S, Shaw BC, Devanney N, Katsumata Y, Press EE, Fardo DW. Evaluation of CD33 as a genetic risk factor for Alzheimer's disease. Acta Neuropathol. 2019 138:187-199.PMID: 30949760
Parikh IJ, Estus JL, Zajac DJ, Malik M, Maldonado Weng J, Tai LM, Chlipala GE, LaDu MJ, Green SJ, Estus S. Murine Gut Microbiome Association With APOE Alleles. Front Immunol. 2020;11:200. PMID: 32117315
Shaw BC and Estus S. Pseudogene-Mediated Gene Conversion After CRISPR-Cas9 Editing Demonstrated by Partial CD33 Conversion with SIGLEC22P. CRISPR J. 2021. doi: 10.1089/crispr.2021.0052. PMID: 34558988
Shaw BC, Katsumata Y, Simpson JF, Fardo DW, Estus S. Analysis of Genetic Variants Associated with Levels of Immune Modulating Proteins for Impact on Alzheimer's Disease Risk Reveal a Potential Role for SIGLEC14. Genes (Basel). 2021;12(7):1008. PMID: 34208838
Zajac, DJ, Green SJ, Johnson LA, Estus S. APOE genetics influence murine gut microbiome. Sci Rep. 2022, 12:1906. PMID: 35115575
Shaw BC, Snider HC, Turner AK, Zajac DJ, Simpson JF, Estus S. An Alternatively Spliced TREM2 Isoform Lacking the Ligand Binding Domain is Expressed in Human Brain. J Alzheimer’s Dis. 2022;87(4):1647-1657. PMID: 35527547
Zajac DJ, Shaw BC, Braun DJ, Green SJ, Morganti J and Estus S. Exogenous Short Chain Fatty Acid Effects in APP/PS1 Mice . Front. Neuro. 2022; 16: 873549. PMID: 35860296