Psychiatric diseases are devastating and poorly understood. The goal of this project is to ? identify the cell biological phenotypes that underlie autism and other psychiatric? disorders, taking advantage of new developments in human stem cell technology. I? propose to harvest skin fibroblasts from patients with autism, to reprogram these cells to? generate induced pluripotent stem (iPS) cells, and to differentiate the iPS cells into? neurons. I will then use a set of semi-automated in vitro assays to develop a phenotypic? fingerprint for each cell line focusing on the developmental and functional phenotypes? that are likely to lead to autism. We will use automated microscopes, cell sorters and? semi-automated patch clamps to measure the differentiation, migration, survival,? morphology, and excitability of neurons derived from patients. Finally, we will take? advantage of the genetic information available for some autistic patients to determine? whether deletion, duplication, or mutation of specific genes leads the phenotypes? observed in the neurons from that patient. This approach has the potential to? revolutionize our study of autism and other psychiatric disorders. It will allow us to link? the phenotype and genotype of patients with the cell biological defects that give rise to? disease. In addition, it will allow us to develop cell-based assays to both investigate the? etiology of the disease and to find new treatments for these untreatable disorders.
| Tsuruta, Fuminori; Dolmetsch, Ricardo E (2015) PIKfyve mediates the motility of late endosomes and lysosomes in neuronal dendrites. Neurosci Lett 605:18-23 |
| Yang, Mu; Mahrt, Elena J; Lewis, Freeman et al. (2015) 16p11.2 Deletion Syndrome Mice Display Sensory and Ultrasonic Vocalization Deficits During Social Interactions. Autism Res 8:507-21 |
| Byers, Blake; Lee, Hyun Joo; Liu, Jia et al. (2015) Direct in vivo assessment of human stem cell graft-host neural circuits. Neuroimage 114:328-37 |
| Pa?ca, Sergiu P; Panagiotakos, Georgia; Dolmetsch, Ricardo E (2014) Generating human neurons in vitro and using them to understand neuropsychiatric disease. Annu Rev Neurosci 37:479-501 |
| Sadaghiani, Amir Masoud; Lee, Sang Min; Odegaard, Justin I et al. (2014) Identification of Orai1 channel inhibitors by using minimal functional domains to screen small molecule microarrays. Chem Biol 21:1278-1292 |
| Shcheglovitov, Aleksandr; Shcheglovitova, Olesya; Yazawa, Masayuki et al. (2013) SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503:267-71 |
| Yazawa, Masayuki; Dolmetsch, Ricardo E (2013) Modeling Timothy syndrome with iPS cells. J Cardiovasc Transl Res 6:1-9 |
| Krey, Jocelyn F; Pa?ca, Sergiu P; Shcheglovitov, Aleksandr et al. (2013) Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat Neurosci 16:201-9 |
| Wang, Yanling; Dolmetsch, Ricardo (2013) In vitro human corticogenesis. Neuron 77:379-81 |
| Pa?ca, Sergiu P; Portmann, Thomas; Voineagu, Irina et al. (2011) Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 17:1657-62 |
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