The mammalian nervous system is composed of a multitude of distinct neuronal subtypes, each with its own phenotype and differential sensitivity to degenerative disease. Although some specific neuronal types can be isolated from intact rodent embryos or engineered from stem cells for translational studies, these approaches are time-consuming and many neuronal subtypes are inaccessible. Transcription factor-mediated reprogramming might provide a more direct route to the generation of neurons for disease modeling and regenerative medicine, but it is currently unclear if this approach can be used to create cells with translational utility. Here, we propose to identify a set of transcription factors sufficient to convert fibroblasts into functional spinal motor neurons. We will characterize the reprogramming process and examine the molecular and functional properties of the resulting motor neurons in order to determine their therapeutic potential. These studies will provide an accessible source of patient-specific motor neurons for the study of neurodegenerative disease, demonstrate that specific adult cell types can be directly generated from somatic cells using defined factors, and mechanistically dissect the defined-factor reprogramming process.

Public Health Relevance

The mammalian nervous system is composed of a multitude of distinct neuronal subtypes, each with its own phenotype and differential sensitivity to degenerative disease and although some specific neuronal types can be isolated from intact rodent embryos or engineered from stem cells for translational studies, these approaches are time-consuming and many neuronal subtypes are inaccessible. The goal of these studies is to identify a small group of defined transcription factors can convert fibroblasts directly into motor neurons, thereby enabling the rapid generation of these cells for therapeutic use. More broadly, these studies will investigate the potential of using defined-factor reprogramming to create specific adult cell types with translational utility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
4R00NS077435-03
Application #
8605244
Study Section
Special Emphasis Panel (NSS)
Program Officer
Owens, David F
Project Start
2013-01-01
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
3
Fiscal Year
2013
Total Cost
$249,000
Indirect Cost
$62,049
Name
University of Southern California
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Wilkinson, Brent; Evgrafov, Oleg V; Zheng, DongQing et al. (2018) Endogenous Cell Type-Specific Disrupted in Schizophrenia 1 Interactomes Reveal Protein Networks Associated With Neurodevelopmental Disorders. Biol Psychiatry :
Shi, Yingxiao; Lin, Shaoyu; Staats, Kim A et al. (2018) Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med 24:313-325
Ichida, Justin K; Staats, Kim A; Davis-Dusenbery, Brandi N et al. (2018) Comparative genomic analysis of embryonic, lineage-converted and stem cell-derived motor neurons. Development 145:
Kaneda, Shohei; Kawada, Jiro; Akutsu, Hidenori et al. (2017) Compartmentalized embryoid body culture for induction of spatially patterned differentiation. Biomicrofluidics 11:041101
Patten, Shunmoogum A; Aggad, Dina; Martinez, Jose et al. (2017) Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis. JCI Insight 2:
Gopalakrishnan, Suhasni; Hor, Pooja; Ichida, Justin K (2017) New approaches for direct conversion of patient fibroblasts into neural cells. Brain Res 1656:2-13
Pepper, Jon-Paul; Wang, Tiffany V; Hennes, Valerie et al. (2017) Human Induced Pluripotent Stem Cell-Derived Motor Neuron Transplant for Neuromuscular Atrophy in a Mouse Model of Sciatic Nerve Injury. JAMA Facial Plast Surg 19:197-205
Toma, Jeremy S; Shettar, Basavaraj C; Chipman, Peter H et al. (2015) Motoneurons derived from induced pluripotent stem cells develop mature phenotypes typical of endogenous spinal motoneurons. J Neurosci 35:1291-306
Wainger, Brian J; Buttermore, Elizabeth D; Oliveira, Julia T et al. (2015) Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts. Nat Neurosci 18:17-24
Wen, Xinmei; Tan, Wenzhi; Westergard, Thomas et al. (2014) Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 84:1213-25

Showing the most recent 10 out of 20 publications