Professor of Pharmacology and Toxicology
Dean of the College of Pharmacy
Zebrafish, Phenotypic Screening, Behavior, Neuropharmacology, Disease Models, Genome Editing, Therapeutics
Small molecules are powerful tools for studying developmental biology because they provide timing and dosage control over developmental pathways that is difficult to achieve with genetic mutations. Unfortunately, only a handful of developmental pathways can currently be targeted with small molecules. We are discovering novel chemical modifiers of developmental pathways by exposing zebrafish embryos to libraries of structurally diverse small molecules and identifying those that induce specific developmental defects. Using screens of this type, we have discovered dozens of compounds that cause specific defects in hematopoesis, cardiac physiology, embryonic patterning, pigmentation, and morphogenesis of the heart, brain, ear, and eye and germ cell lineage.
One focus of our group is modeling human diseases in zebrafish. We then use the models to screen large chemical libraries for small molecule modulators of the disease-related phenotypes. The compounds we discover help us elucidate disease mechanisms and serve as starting points for developing new drug candidates.
Disease physiology is often complex and involves interactions between multiple organs and tissue types. Consequently, many diseases cannot be studied effectively using in vitro assays. The zebrafish is an excellent vertebrate model system to study many complex, non-cell autonomous diseases because the diseases can be studied in a native, whole-organism setting. In addition, compounds discovered in zebrafish screens have the advantage of having been selected for their ability to be active, efficacious, and well tolerated in animals.
Neuroscience & Behavior
Behaviors are accessible readouts of the molecular pathways that control neuronal signaling. Our group develops tools and techniques for comprehensive and high-throughput behavioral phenotyping in the zebrafish. These tools have some potential to improve our understanding of the neuronal signlaing and may accelerate the pace of neuroactive drug discovery.
References (Selected Publications)
- Parvez S, Herdman C, Beerens M, Chakraborti K, Harmer ZP, Yeh JJ, MacRae CA, Yost HJ, Peterson RT. MIC-Drop: A platform for large-scale in vivo CRISPR screens. Science. 2021; eabi8870. doi: 10.1126/science.abi8870. Online ahead of print.
- Amgalan D, Garner TP, Pekson R, Jia XF, Yanamandala M, Paulino V, Liang FG, Corbalan JJ, Lee J, Chen Y, Karagiannis GS, Sanchez LR, Liang H, Narayanagari SR, Mitchell K, Lopez A, Margulets V, Scarlata M, Santulli G, Asnani A, Peterson RT, Hazan RB, Condeelis JS, Oktay MH, Steidl U, Kirshenbaum LA, Gavathiotis E, Kitsis RN. A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy. Nature Cancer. 2020;1(3):315-328.
- Lam PY, Thawani AR, Balderas E, White AJP, Chaudhuri D, Fuchter MJ, Peterson RT. TRPswitch-A Step-Function Chemo-optogenetic Ligand for the Vertebrate TRPA1 Channel. J Am Chem Soc. 2020;142(41):17457-17468.
- McCarroll MN, Gendelev L, Kinser R, Taylor J, Bruni G, Myers-Turnbull D, Helsell C, Carbajal A, Rinaldi C, Kang HJ, Gong JH, Sello JK, Tomita S, Peterson RT, Keiser MJ, Kokel D. Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation. Nature Commun. 2019;10(1):4078.
- Jin YN, Schlueter PJ, Jurisch-Yaksi N, Lam PY, Jin S, Hwang WY, Yeh JJ, Yoshigi M, Ong SE, Schenone M, Hartigan CR, Carr SA, Peterson RT. Noncanonical translation via deadenylated 3' UTRs maintains primordial germ cells. Nature Chem Biol. 2018; (9):844-852.
- Rennekamp AJ, Huang XP, Wang Y, Patel S, Lorello PJ, Cade L, Gonzales APW, Yeh JRJ, Caldarone BJ, Roth BL, Kokel D, Peterson RT. σ1 receptor ligands control a switch between passive and active threat responses. Nature Chem Biol. 2016;12(7):552-8.
- Bruni G, Rennekamp AJ, Velenich A, McCarroll M, Gendelev L, Lakhani P, Lensen D, Evron T, Lorello PJ, Huang XP, Kolczewski S, Carey G, Caldarone BJ, Prinssen E, Roth BL, Keiser MJ, Peterson RT, Kokel D. Systematic behavioral profiling identifies antipsychotic-like compounds with multi-target polypharmacology. Nature Chem Biol. 2016;12(7):559-66.
- Kleinstiver BP, Prew MS, Tsai SQ, Topkar VV, Nguyen NT, Zheng Z, Gonzales APW, Li Z, Peterson RT, Yeh JRJ, Aryee MJ, Joung JK. Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature. 2015; 523(7561):481-5.
- Liu Y, Asnani A, Zou L, Bentley VL, Yu M, Wang Y, Dellaire G, Sarkar KS, Dai M, Chen HH, Sosnovik DE, Shin JT, Haber DA, Berman JN, Chao W, Peterson RT. Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase. Science Transl Med. 2014; 6, 266ra170.
- Hwang WY, Fu Y, Reyon D, Maeder ML, Tsai SQ, Sander JD, Peterson RT, Yeh J-RJ, Joung JK. Efficient genome editing in zebrafish using a CRISPR-Cas system. Nature Biotechnol. 2013; 31(3):227-9.
- Kokel D, Cheung CYJ, Mills R, Coutinho-Budd J, Huang L, Setola V, Sprague J, Jin S, Jin YN, Huang X-P, Bruni G, Woolf CJ, Roth BL, Hamblin MR, Zylka MJ, Milan DJ, Peterson RT. Photochemical activation of TRPA1 channels in neurons and animals. Nature Chem Biol. 2013; 9(4):257-63.
- Sander JD, Cade L, Khayter C, Reyon D, Peterson RT, Joung JK, Yeh JR. Targeted gene disruption in somatic zebrafish cells using engineered TALENs. Nature Biotechnol. 2011;29(8):697-8.
- Laggner C, Kokel D, Setola V, Tolia A, Lin H, Irwin JJ, Keiser MJ, Cheung CY, Minor DL Jr, Roth BL, Peterson RT, Shoichet BK. Chemical informatics and target identification in a zebrafish phenotypic screen. Nature Chem Biol. 2011;8(2):144-6.
- Kokel D, Bryan J, Laggner C, White R, Cheung CY, Mateus R, Healey D, Kim S, Werdich AA, Haggarty SJ, Macrae CA, Shoichet B, Peterson RT. Rapid behavior-based identification of neuroactive small molecules in the zebrafish. Nature Chem Biol. 2010; 6(3):231-237.
- Rihel J, Prober DA, Arvanites A, Lam K, Zimmerman S, Jang S, Haggarty SJ, Kokel D, Rubin LL, Peterson RT, Schier AF. Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation. Science. 2010; 327(5963):348-51.