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Research at Mass General
Randall T. Peterson, MDAssociate Professor of Medicine Harvard Medical School
Assistant in BiologyMassachusetts General Hospital
The Peterson laboratory focuses on discovering bioactive small molecules by high-throughput in vivo screening. Whereas chemical screening has traditionally focused on simple, in vitro assays, many biological phenomena are difficult to reduce to an in vitro assay. The Peterson lab is using the tools of chemical biology to investigate these complex in vivo phenomena. By conducting high-throughput screens with intact, living zebraﬁsh, we can discover small molecules that alter virtually any biological process. The lab is applying this approach in three areas: 1) developmental biology, including cardiovascular development and germ cell development; 2) disease physiology, including heart failure, anemia and leukemia; and 3) animal behaviors. In each of these areas, the novel small molecules discovered are providing new biological insights and/or novel therapeutic opportunities.
Randall T. Peterson, MDPrincipal Inverigator
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 hematopoiesis, embryonic patterning, pigmentation, and morphogenesis of the heart, brain, ear and eye and germ cell lineage.
One notable lab success in recent years has been the discovery of dorsomorphin and related BMP receptor antagonists. These small molecules were discovered during a zebraﬁsh screen for compounds that alter development of the embryonic dorsal-ventral axis. As the ﬁrst compounds to antagonize BMP signaling, the molecules have become powerful tools for studying BMP functions, and the molecules have already been used in hundreds of other studies around the world. In addition, the compounds have proven to be effective in treating animal models of BMP-related disorders, including heterotopic ossiﬁcation and anemia. The compounds are currently in late stages of preclinical development.
One focus of our group is modeling human diseases in zebraﬁsh. We use these 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.
One notable example from the lab was discovery of compounds that suppress the effects of the AML1-ETO oncogene in acute myeloid leukemia (AML). We generated a model of AML by expressing the human AML1-ETO oncogene in zebraﬁsh. These zebraﬁsh accumulate granulocytic blast cells that resemble those found in humans with AML. In a robotic expression screen of thousands of small molecules, we discovered that nimesulide can reverse the oncogenic effects of AML1-ETO, an effect that is conserved in mammalian models of AML.
Behaviors are accessible readouts of the molecular pathways that control neuronal signaling. Our group develops tools and techniques for high-throughput behavioral phenotyping in the zebraﬁsh. These tools have potential to improve our understanding of neuronal signaling and may accelerate the pace of neuroactive drug discovery.
View all publications from the Peterson Lab
Kleinstiver BP, Prew MS, Tsai SQ, Topkar VV, Nguyen NT, Zheng Z, Gonzales AP, Li Z, Peterson RT, Yeh JR, Aryee MJ, Joung JK. Engineered CRISPR-Cas9 nucleases with altered PAM speciﬁcities. Nature. 2015 Jul 23;523(7561):481-5.
Nath AK, Ryu JH, Jin YN, Roberts LD, Dejam A, Gerszten RE, Peterson RT. PTPMT1 inhibition lowers glucose through succinate dehydrogenase phosphorylation. 2015 Feb 4. pii: S2211-1247(15)00023-6.
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. Sci Transl Med. 2014; 6, 266ra170.
Kokel D, Cheung CY, Mills R, Coutinho-Budd J, Huang L, Setola V, Sprague J, Jin S, Jin YN, Huang XP, Bruni G, Woolf CJ, Roth BL, Hamblin MR, Zylka MJ, Milan DJ, Peterson RT. Photochemical activation of TRPA1 channels in neurons and animals. Nat Chem Biol. 9(4):257-63, 2013.
Hwang WY, Fu Y, Reyon D, Maeder ML, Tsai SQ, Sander JD, Peterson RT, Yeh JR, Joung JK. Efficient genome editing in zebraﬁsh using a CRISPR-Cas system. Nat Biotechnol. 31(3): 227-9, 2013.
van Ham TJ, Kokel D, Peterson RT. Apoptotic cells are cleared by directional migration and elmo1- dependent macrophage engulfment. Curr Biol. 22(9):830-6, 2012.
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