This web page was produced as an assignment for Genetics 564, an undergraduate course at UW‐Madison.
Monoamine oxidase A (MAOA) gene has been discovered to be the most compelling candidate for susceptibility for aggression. In human, there are 2R (two repeats), 3R, 3.5R, 4R and 5R variants of a 30-base sequence in the promoter region of the MAOA gene.[1-3] Alleles with 2R, 3R or 5R constitute the low-activity form of MAOA (L-MAOA), whereas alleles with 3.5R and 4R constitute the high-activity form of MAOA (H-MAOA).[1-3] The MAOA gene encodes for MAOA protein, an enzyme that breaks down several neurotransmitters— norepinephrine, epinephrine, serotonin and dopamine.[4] L-MAOA produces less MAOA proteins and causes the mentioned neurotransmitters to build up in excess, thereby leading to increased propensity towards aggression.[1-3] However, supplementation of drugs to suppress aggression in these individuals has not been an option, because the interactions of human MAOA with other proteins are not fully understood.
The SIRT1 gene has been shown to activate the transcription of the MAOA gene in mice.[5] Given this, I hypothesize that upregulation of SIRT1 will increase MAOA levels and suppress aggression. It was discovered that three novel small-molecule activators of SIRT1, namely SRT2183, SRT1460 and SRT1720, are able to increase the expression of SIRT1 in rats and humans.[6] Most importantly, these small-molecule activators are potent, orally bioavailable and active in vivo.[7] I will use rhesus monkeys (Macaca mulatta) to test the hypothesis that small-molecule activators of SIRT1 can increase MAOA level in the brain and suppress aggression. Rhesus monkeys make suitable models as 40% of them carry the L-MAOA allele.[8]
My primary goal is to determine whether the upregulation of SIRT1 (through supplementation of SRT2183, SRT1460 and SRT1720) increases MAOA levels and thus, reduces aggressive behaviors in L-MAOA rhesus monkeys. I will then examine the mechanisms of the interactions between SIRT1 and MAOA in rhesus macaques. The objective of this study is to analyze the feasibility of SRT2183, SRT1460 and SRT1720 as potential drugs to upregulate MAOA and suppress aggression in L-MAOA human.
Specific Aim 1
Determine if SRT2183, SRT1460 and SRT1720 can increase MAOA levels in the brain and reduce aggression levels in L-MAOA rhesus monkeys.
Approach: I will selectively breed highly-aggressive L-MAOA rhesus monkeys, feed them with SRT2183, SRT1460 and SRT1720, access their behavioral changes, and observe the levels of MAOA proteins in their brain samples using quantitative mass spectrometry.
Hypothesis: Supplementation of SRT2183, SRT1460 and SRT1720 will increase MAOA levels in brain and prevent manifestation of aggressive behaviors in rhesus monkeys.
Specific Aim 2
Elucidate the mechanism of how SIRT1 expression affect brain-specific MAOA expression in rhesus monkeys.
Approach: I will extract brain samples of both L-MAOA and H-MAOA rhesus monkeys, then use TAP-tags in conjunction with Y2H system to examine mechanism of how SIRT1 expression affect MAOA expression.
Hypothesis: SIRT1 protein is a key transcriptional upregulator of MAOA gene.
Specific Aim 3
Study the homology of SIRT1 and MAOA variants (both genes and proteins) between rhesus monkeys and humans.
Approach: I will use Roche454 sequencing to determine the variants of SIRT1 and MAOA genes in rhesus monkeys and humans, then compare their homology. For SIRT1 and MAOA proteins, I will use mass spectrometry.
Hypothesis: SIRT1 and MAOA are both very well-conserved in rhesus monkeys and humans, with high similarity in the patterns of polymorphism.
The SIRT1 gene has been shown to activate the transcription of the MAOA gene in mice.[5] Given this, I hypothesize that upregulation of SIRT1 will increase MAOA levels and suppress aggression. It was discovered that three novel small-molecule activators of SIRT1, namely SRT2183, SRT1460 and SRT1720, are able to increase the expression of SIRT1 in rats and humans.[6] Most importantly, these small-molecule activators are potent, orally bioavailable and active in vivo.[7] I will use rhesus monkeys (Macaca mulatta) to test the hypothesis that small-molecule activators of SIRT1 can increase MAOA level in the brain and suppress aggression. Rhesus monkeys make suitable models as 40% of them carry the L-MAOA allele.[8]
My primary goal is to determine whether the upregulation of SIRT1 (through supplementation of SRT2183, SRT1460 and SRT1720) increases MAOA levels and thus, reduces aggressive behaviors in L-MAOA rhesus monkeys. I will then examine the mechanisms of the interactions between SIRT1 and MAOA in rhesus macaques. The objective of this study is to analyze the feasibility of SRT2183, SRT1460 and SRT1720 as potential drugs to upregulate MAOA and suppress aggression in L-MAOA human.
Specific Aim 1
Determine if SRT2183, SRT1460 and SRT1720 can increase MAOA levels in the brain and reduce aggression levels in L-MAOA rhesus monkeys.
Approach: I will selectively breed highly-aggressive L-MAOA rhesus monkeys, feed them with SRT2183, SRT1460 and SRT1720, access their behavioral changes, and observe the levels of MAOA proteins in their brain samples using quantitative mass spectrometry.
Hypothesis: Supplementation of SRT2183, SRT1460 and SRT1720 will increase MAOA levels in brain and prevent manifestation of aggressive behaviors in rhesus monkeys.
Specific Aim 2
Elucidate the mechanism of how SIRT1 expression affect brain-specific MAOA expression in rhesus monkeys.
Approach: I will extract brain samples of both L-MAOA and H-MAOA rhesus monkeys, then use TAP-tags in conjunction with Y2H system to examine mechanism of how SIRT1 expression affect MAOA expression.
Hypothesis: SIRT1 protein is a key transcriptional upregulator of MAOA gene.
Specific Aim 3
Study the homology of SIRT1 and MAOA variants (both genes and proteins) between rhesus monkeys and humans.
Approach: I will use Roche454 sequencing to determine the variants of SIRT1 and MAOA genes in rhesus monkeys and humans, then compare their homology. For SIRT1 and MAOA proteins, I will use mass spectrometry.
Hypothesis: SIRT1 and MAOA are both very well-conserved in rhesus monkeys and humans, with high similarity in the patterns of polymorphism.
References:
- Grimsby, J., Chen, K., Wang, L.J., Lan, N.C., & Shih, J.C. (1991) Human monoamine oxidase A and B genes exhibit identical exon-intron organization. Proceedings of the National Academy of Sciences of the United States of America, 88(9):3637–3641.
- Sabol, S.Z., Hu, S., & Hamer, D. (1998). A functional polymorphism in the monoamine oxidase A gene promoter. Human Genetics, 103(3), 273–9.
- Beaver, K. M., Wright, J. P., Boutwell, B. B., Barnes, J., Delisi, M., & Vaughn, M. G. (2013). Exploring the association between the 2-repeat allele of the MAOA gene promoter polymorphism and psychopathic personality traits, arrests, incarceration, and lifetime antisocial behavior. Personality and Individual Differences, 54(2), 164-168.
- Guo, G., Ou, X., Roettger, M., & Shih, J. C. (2008). The VNTR 2 repeat in MAOA and delinquent behavior in adolescence and young adulthood: associations and MAOA promoter activity. European Journal of Human Genetics, 16(5), 626-634.
- Libert, S., Rubio, J. P., Asara, J., Cohen, D., Das, A., Bell, E., et al. (2011). SIRT1 Activates MAO-A in the Brain to Mediate Anxiety and Exploratory Drive. Cell, 147(7), 1459-1472.
- Milne, J. C., Lynch, A. V., Olefsky, J. M., Jirousek, M. R., Elliott, P. J., Nunes, J. J., et al. (2007). Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature, 450(7170), 712-716.
- Milne, J. C., & Denu, J. M. (2008). The Sirtuin family: therapeutic targets to treat diseases of aging. Current Opinion in Chemical Biology, 12(1), 11-17.
- Wendland, J. R., Hampe, M., Newman, T. K., Syagailo, Y., Meyer, J., Schempp, W., Timme, A., Suomi, S. J. and Lesch, K. P. (2006), Structural variation of the monoamine oxidase A gene promoter repeat polymorphism in nonhuman primates. Genes, Brain and Behavior, 5: 40–45.
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