I. Pioneer a new approach for drug target discovery that has implications for a broad range of developmental and chronic illnesses. II. Develop a robust technology platform for large-scale targeted genomic engineering to enable more complete recapitulation of human disease genotypes in animal models. We will enable precise introduction of combinations of disease-associated genetic mutations into a single animal model. III. Develop a technology for targeted epigenome modification to enable direct functional testing of causal links between specific epigenetic modifications and disease pathophysiology. IV. Identify fundamentally new classes of therapeutics for major depression.
Major depressive disorder is a devastating mental illness affecting millions of Americans annually, with a large fraction of patients unresponsive to available therapies. The proposed project aims to identify fundamentally new classes of therapeutics by probing the epigenetic mechanisms contributing to major depression, through a combination of innovative technology development, and systematically establishing causal links between epigenetic targets and disease phenotype. The technologies developed through this proposal will establish a new epigenetic paradigm for drug discovery and have broad impacts for many fields of biomedical research including cancer, diabetes, obesity, and other neurological disorders. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES. COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested.
|Slaymaker, Ian M; Gao, Linyi; Zetsche, Bernd et al. (2016) Rationally engineered Cas9 nucleases with improved specificity. Science 351:84-8|
|Tabebordbar, Mohammadsharif; Zhu, Kexian; Cheng, Jason K W et al. (2016) In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351:407-11|
|Yamano, Takashi; Nishimasu, Hiroshi; Zetsche, Bernd et al. (2016) Crystal Structure of Cpf1 in Complex with Guide RNA and Target DNA. Cell 165:949-62|
|Sanjana, Neville E; Wright, Jason; Zheng, Kaijie et al. (2016) High-resolution interrogation of functional elements in the noncoding genome. Science 353:1545-1549|
|Hirano, Hisato; Gootenberg, Jonathan S; Horii, Takuro et al. (2016) Structure and Engineering of Francisella novicida Cas9. Cell 164:950-61|
|Jain, Isha H; Zazzeron, Luca; Goli, Rahul et al. (2016) Hypoxia as a therapy for mitochondrial disease. Science 352:54-61|
|Abudayyeh, Omar O; Gootenberg, Jonathan S; Konermann, Silvana et al. (2016) C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector. Science 353:aaf5573|
|Nelson, Christopher E; Hakim, Chady H; Ousterout, David G et al. (2016) In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351:403-7|
|Heidenreich, Matthias; Zhang, Feng (2016) Applications of CRISPR-Cas systems in neuroscience. Nat Rev Neurosci 17:36-44|
|Zhou, Yang; Kaiser, Tobias; Monteiro, PatrÃcia et al. (2016) Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects. Neuron 89:147-62|
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