As we enter into an era of personalized (precision) medicine, it becomes increasingly important to define the factors that confer disease risk and outcome. Since these determinants cannot be easily controlled in human epidemiological studies, genetically-engineered mouse (GEM) strains and human induced pluripotent stem cell (iPSC) lines provide mechanistically-tractable platforms to define the factors underlying disease heterogeneity and translate them to risk assessment tools and treatments. This challenge is nicely illustrated by Neurofibromatosis type 1 (NF1), a rare neurogenetic condition caused by a germline mutation in the NF1 gene. Individuals with NF1 are prone to the development of a wide variety of neurological problems, including cognitive and behavioral problems (60-70% of children) and low-grade brain tumors (~20% of children). While establishing the diagnosis of NF1 in an infant is straightforward, it is currently not possible to predict which child will develop future medical problems, determine whether there will be clinical progression requiring treatment, or institute effective therapies that specifically target the subtype of clinical manifestation in that individual. The pressing challenge for clinicians and researchers alike is to dissect the genetic, cellular, molecular, and systems-level etiologies for these common neurologic problems with the ultimate goal of developing prognostic and precision neurology approaches for children affected with NF1. In this proposal, we plan to leverage human NF1-patient iPSCs, mice engineered with patient germline NF1 gene mutations, bioinformatics and systems biology approaches, and novel modeling approaches to mechanistically define the factors that underlie the heterogeneity that characterizes NF1. The overall mission of this project is to establish the etiologic bases for NF1 clinical variability and to create a blueprint for future clinical application necessary to transform the care of individuals with NF1 from a reactive to a more proactive approach.
Impact This project employs novel Nf1 mouse strains, human iPSC lines, and converging experimental methodologies to define the risk factors and etiologies that dictate the development, clinical course, and treatment response of neurological dysfunction in children with NF1 with translatability to future precision medicine strategies.
|Freret, Morgan E; Anastasaki, Corina; Gutmann, David H (2018) Independent NF1 mutations underlie café-au-lait macule development in a woman with segmental NF1. Neurol Genet 4:e261|
|Morris, Stephanie M; Gutmann, David H (2018) A genotype-phenotype correlation for quantitative autistic trait burden in neurofibromatosis 1. Neurology 90:377-379|
|Pan, Yuan; Duron, Christina; Bush, Erin C et al. (2018) Graph complexity analysis identifies an ETV5 tumor-specific network in human and murine low-grade glioma. PLoS One 13:e0190001|
|Pan, Yuan; Xiong, Min; Chen, Ran et al. (2018) Athymic mice reveal a requirement for T-cell-microglia interactions in establishing a microenvironment supportive of Nf1 low-grade glioma growth. Genes Dev 32:491-496|
|Bai, Lei; Lee, Yool; Hsu, Cynthia T et al. (2018) A Conserved Circadian Function for the Neurofibromatosis 1 Gene. Cell Rep 22:3416-3426|
|Campen, Cynthia J; Gutmann, David H (2018) Optic Pathway Gliomas in Neurofibromatosis Type 1. J Child Neurol 33:73-81|
|Maloney, Susan E; Chandler, Krystal C; Anastasaki, Corina et al. (2018) Characterization of early communicative behavior in mouse models of neurofibromatosis type 1. Autism Res 11:44-58|
|Wegscheid, Michelle L; Anastasaki, Corina; Gutmann, David H (2018) Human stem cell modeling in neurofibromatosis type 1 (NF1). Exp Neurol 299:270-280|
|Chen, Ran; Pan, Yuan; Gutmann, David H (2017) The power of the few. Genes Dev 31:1177-1179|
|Chheda, Milan G; Gutmann, David H (2017) Using Epigenetic Reprogramming to Treat Pediatric Brain Cancer. Cancer Cell 31:609-611|
Showing the most recent 10 out of 15 publications