@article{gabrawy_khosravian_morcos_morozova_jezek_walston_huang_abadir_leips_2022, title={Genome-Wide Analysis in Drosophila Reveals the Genetic Basis of Variation in Age-Specific Physical Performance and Response to ACE Inhibition}, volume={13}, ISSN={["2073-4425"]}, DOI={10.3390/genes13010143}, abstractNote={Despite impressive results in restoring physical performance in rodent models, treatment with renin–angiotensin system (RAS) inhibitors, such as Lisinopril, have highly mixed results in humans, likely, in part, due to genetic variation in human populations. To date, the genetic determinants of responses to drugs, such as RAS inhibitors, remain unknown. Given the complexity of the relationship between physical traits and genetic background, genomic studies which predict genotype- and age-specific responses to drug treatments in humans or vertebrate animals are difficult. Here, using 126 genetically distinct lines of Drosophila melanogaster, we tested the effects of Lisinopril on age-specific climbing speed and endurance. Our data show that functional response and sensitivity to Lisinopril treatment ranges from significant protection against physical decline to increased weakness depending on genotype and age. Furthermore, genome-wide analyses led to identification of evolutionarily conserved genes in the WNT signaling pathway as being significantly associated with variations in physical performance traits and sensitivity to Lisinopril treatment. Genetic knockdown of genes in the WNT signaling pathway, Axin, frizzled, nemo, and wingless, diminished or abolished the effects of Lisinopril treatment on climbing speed traits. Our results implicate these genes as contributors to the genotype- and age-specific effects of Lisinopril treatment and because they have orthologs in humans, they are potential therapeutic targets for improvement of resiliency. Our approach should be widely applicable for identifying genomic variants that predict age- and sex-dependent responses to any type of pharmaceutical treatment.}, number={1}, journal={GENES}, author={Gabrawy, Mariann M. and Khosravian, Nick and Morcos, George S. and Morozova, Tatiana V. and Jezek, Meagan and Walston, Jeremy D. and Huang, Wen and Abadir, Peter M. and Leips, Jeff}, year={2022}, month={Jan} }
 @article{gabrawy_campbell_carbone_morozova_arya_turlapati_walston_starz-gaiano_everett_mackay_et al._2019, title={Lisinopril Preserves Physical Resilience and Extends Life Span in a Genotype-Specific Manner in Drosophila melanogaster}, volume={74}, ISSN={["1758-535X"]}, DOI={10.1093/gerona/glz152}, abstractNote={Abstract
               Physical resiliency declines with age and comorbid conditions. In humans, angiotensin-converting enzyme (ACE) has been associated with attenuation of the decline in physical performance with age. ACE-inhibitor compounds, commonly prescribed for hypertension, often have beneficial effects on physical performance however the generality of these effects are unclear. Here, we tested the effects of the ACE-inhibitor Lisinopril on life span, and age-specific speed, endurance, and strength using three genotypes of the Drosophila melanogaster Genetic Reference Panel. We show that age-related decline in physical performance and survivorship varies with genetic background. Lisinopril treatment increased mean life span in all Drosophila Genetic Reference Panel lines, but its effects on life span, speed, endurance, and strength depended on genotype. We show that genotypes with increased physical performance on Lisinopril treatment experienced reduced age-related protein aggregation in muscle. Knockdown of skeletal muscle-specific Ance, the Drosophila ortholog of ACE, abolished the effects of Lisinopril on life span, implying a role for skeletal muscle Ance in survivorship. Using transcriptome profiling, we identified genes involved in stress response that showed expression changes associated with genotype and age-dependent responsiveness to Lisinopril. Our results demonstrate that Ance is involved in physical decline and demonstrate genetic variation in phenotypic responses to an ACE inhibitor.}, number={12}, journal={JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES}, author={Gabrawy, Mariann M. and Campbell, Sarah and Carbone, Mary Anna and Morozova, Tatiana V and Arya, Gunjan H. and Turlapati, Lavanya B. and Walston, Jeremy D. and Starz-Gaiano, Michelle and Everett, Logan and Mackay, Trudy F. C. and et al.}, year={2019}, month={Dec}, pages={1844–1852} }
 @article{bushnell_ward_morozova_oshiro_lin_judson_hester_mckee_higuchi_2017, title={Genetic Targets of Acute Toluene Inhalation in Drosophila melanogaster}, volume={156}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfw243}, abstractNote={Interpretation and use of data from high-throughput assays for chemical toxicity require links between effects at molecular targets and adverse outcomes in whole animals. The well-characterized genome of Drosophila melanogaster provides a potential model system by which phenotypic responses to chemicals can be mapped to genes associated with those responses, which may in turn suggest adverse outcome pathways associated with those genes. To determine the utility of this approach, we used the Drosophila Genetics Reference Panel (DGRP), a collection of ∼200 homozygous lines of fruit flies whose genomes have been sequenced. We quantified toluene-induced suppression of motor activity in 123 lines of these flies during exposure to toluene, a volatile organic compound known to induce narcosis in mammals via its effects on neuronal ion channels. We then applied genome-wide association analyses on this effect of toluene using the DGRP web portal (http://dgrp2.gnets.ncsu.edu), which identified polymorphisms in candidate genes associated with the variation in response to toluene exposure. We tested ∼2 million variants and found 82 polymorphisms located in or near 66 candidate genes that were associated with phenotypic variation for sensitivity to toluene at P < 5 × 10-5, and human orthologs for 52 of these candidate Drosophila genes. None of these orthologs are known to be involved in canonical pathways for mammalian neuronal ion channels, including GABA, glutamate, dopamine, glycine, serotonin, and voltage sensitive calcium channels. Thus this analysis did not reveal a genetic signature consistent with processes previously shown to be involved in toluene-induced narcosis in mammals. The list of the human orthologs included Gene Ontology terms associated with signaling, nervous system development and embryonic morphogenesis; these orthologs may provide insight into potential new pathways that could mediate the narcotic effects of toluene.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Bushnell, Philip J. and Ward, William O. and Morozova, Tatiana V. and Oshiro, Wendy M. and Lin, Mimi T. and Judson, Richard S. and Hester, Susan D. and Mckee, John M. and Higuchi, Mark}, year={2017}, month={Mar}, pages={230–239} }
 @article{swarup_morozova_sridhar_nokes_anholt_2014, title={Modulation of Feeding Behavior by Odorant-Binding Proteins in Drosophila melanogaster}, volume={39}, ISSN={["1464-3553"]}, DOI={10.1093/chemse/bjt061}, abstractNote={Nutrient intake and avoidance of toxins are essential for survival and controlled by attractive and aversive feeding responses. Drosophila melanogaster presents one of the best characterized systems for studies on chemosensation, which is mediated by multigene families of chemoreceptors, including olfactory receptors, gustatory receptors, and odorant-binding proteins (OBPs). Although the response profiles of gustatory receptors have been well studied, the contribution of OBPs to food intake is largely unknown. As most aversive (“bitter”) tastants are hydrophobic, we hypothesized that OBPs may fulfill an essential function in transporting bitter tastants to gustatory receptors to modulate feeding behavior. Here, we used 16 RNAi lines that inhibit expression of individual target Obp genes and show that OBPs modulate sucrose intake in response to a panel of nine bitter compounds. Similar to their function in olfaction, OBPs appear to interact with bitter compounds in a combinatorial and sex-dependent manner. RNAi-mediated reduction in expression of individual Obp genes resulted either in enhanced or reduced intake of sucrose in the presence of bitter compounds, consistent with roles for OBPs in transporting tastants to bitter taste receptors, sequestering them to limit their access to these receptors, or interacting directly with gustatory neurons that respond to sucrose.}, number={2}, journal={CHEMICAL SENSES}, author={Swarup, Shilpa and Morozova, Tatiana V. and Sridhar, Sruthipriya and Nokes, Michael and Anholt, Robert R. H.}, year={2014}, month={Feb}, pages={125–132} }
 @article{morozova_ayroles_jordan_duncan_carbone_lyman_stone_govindaraju_ellison_mackay_et al._2009, title={Alcohol Sensitivity in Drosophila: Translational Potential of Systems Genetics}, volume={183}, ISSN={["1943-2631"]}, DOI={10.1534/genetics.109.107490}, abstractNote={AbstractIdentification of risk alleles for human behavioral disorders through genomewide association studies (GWAS) has been hampered by a daunting multiple testing problem. This problem can be circumvented for some phenotypes by combining genomewide studies in model organisms with subsequent candidate gene association analyses in human populations. Here, we characterized genetic networks that underlie the response to ethanol exposure in Drosophila melanogaster by measuring ethanol knockdown time in 40 wild-derived inbred Drosophila lines. We associated phenotypic variation in ethanol responses with genomewide variation in gene expression and identified modules of correlated transcripts associated with a first and second exposure to ethanol vapors as well as the induction of tolerance. We validated the computational networks and assessed their robustness by transposon-mediated disruption of focal genes within modules in a laboratory inbred strain, followed by measurements of transcript abundance of connected genes within the module. Many genes within the modules have human orthologs, which provides a stepping stone for the identification of candidate genes associated with alcohol drinking behavior in human populations. We demonstrated the potential of this translational approach by identifying seven intronic single nucleotide polymorphisms of the Malic Enzyme 1 (ME1) gene that are associated with cocktail drinking in 1687 individuals of the Framingham Offspring cohort, implicating that variation in levels of cytoplasmic malic enzyme may contribute to variation in alcohol consumption.}, number={2}, journal={GENETICS}, author={Morozova, Tatiana V. and Ayroles, Julien F. and Jordan, Katherine W. and Duncan, Laura H. and Carbone, Mary Anna and Lyman, Richard E. and Stone, Eric A. and Govindaraju, Diddahally R. and Ellison, R. Curtis and Mackay, Trudy F. C. and et al.}, year={2009}, month={Oct}, pages={733–745} }
 @article{garlapow_everett_zhou_gearhart_fay_huang_morozova_arya_turlapati_st armour_et al., title={Genetic and genomic response to selection for food consumption in Drosophila melanogaster}, volume={47}, number={2}, journal={Behavior Genetics}, author={Garlapow, M. E. and Everett, L. J. and Zhou, S. S. and Gearhart, A. W. and Fay, K. A. and Huang, W. and Morozova, T. V. and Arya, G. H. and Turlapati, L. and St Armour, G. and et al.}, pages={227–243} }
 @misc{morozova_mackay_anholt, title={Genetics and genomics of alcohol sensitivity}, volume={289}, number={3}, journal={Molecular Genetics and Genomics}, author={Morozova, T. V. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={253–269} }
 @article{fochler_morozova_davis_gearhart_huang_mackay_anholt, title={Genetics of alcohol consumption in Drosophila melanogaster}, volume={16}, number={7}, journal={Genes Brain and Behavior}, author={Fochler, S. and Morozova, T. V. and Davis, M. R. and Gearhart, A. W. and Huang, W. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={675–685} }
 @article{shorter_dembeck_everett_morozova_arya_turlapati_st armour_schal_mackay_anholt, title={Obp56h modulates mating behavior in Drosophila melanogaster}, volume={6}, number={10}, journal={G3-Genes Genomes Genetics}, author={Shorter, J. R. and Dembeck, L. M. and Everett, L. J. and Morozova, T. V. and Arya, G. H. and Turlapati, L. and St Armour, G. E. and Schal, C. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={3335–3342} }
 @article{carbone_ayroles_yamamoto_morozova_west_magwire_mackay_anholt, title={Overexpression of myocilin in the Drosophila eye activates the unfolded protein response: Implications for glaucoma}, volume={4}, number={1}, journal={PLoS One}, author={Carbone, M. A. and Ayroles, J. F. and Yamamoto, A. and Morozova, T. V. and West, S. A. and Magwire, M. M. and Mackay, T. F. C. and Anholt, R. R. H.} }
 @article{morozova_anholt_mackay, title={Phenotypic and transcriptional response to selection for alcohol sensitivity in Drosophila melanogaster}, volume={8}, number={10}, journal={Genome Biology}, author={Morozova, T. V. and Anholt, R. R. and MacKay, T. F.} }
 @article{morozova_huang_pray_whitham_anholt_mackay, title={Polymorphisms in early neurodevelopmental genes affect natural variation in alcohol sensitivity in adult drosophila}, volume={16}, journal={BMC Genomics}, author={Morozova, T. V. and Huang, W. and Pray, V. A. and Whitham, T. and Anholt, R. R. H. and Mackay, T. F. C.} }
 @article{zhou_morozova_hussain_luoma_mccoy_yamamoto_mackay_anholt, title={The genetic basis for variation in sensitivity to lead toxicity in Drosophila melanogaster}, volume={124}, number={7}, journal={Environmental Health Perspectives}, author={Zhou, S. S. and Morozova, T. V. and Hussain, Y. N. and Luoma, S. E. and McCoy, L. and Yamamoto, A. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={1062–1070} }
 @misc{morozova_goldman_mackay_anholt, title={The genetic basis of alcoholism: Multiple phenotypes, many genes, complex networks}, volume={13}, number={2}, journal={Genome Biology}, author={Morozova, T. V. and Goldman, D. and Mackay, T. F. C. and Anholt, R. R. H.} }
 @article{morozova_mackay_anholt, title={Transcriptional networks for alcohol sensitivity in drosophila melanogaster}, volume={187}, number={4}, journal={Genetics}, author={Morozova, T. V. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={1193–345} }
 @article{morozova_anholt_mackay, title={Transcriptional response to alcohol exposure in Drosophila melanogaster}, volume={7}, number={10}, journal={Genome Biology}, author={Morozova, T. V. and Anholt, R. R. H. and MacKay, T. F. C.} }