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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
5R35NS097211-02
Application #
9392591
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Morris, Jill A
Project Start
2016-12-01
Project End
2024-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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