# Defining the Mechanistic Basis for Neurofibromatosis-1 Nervous System Disease Heterogeneity

> **NIH NIH R35** · WASHINGTON UNIVERSITY · 2021 · $686,252

## Abstract

Project Summary
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.

## Key facts

- **NIH application ID:** 10062526
- **Project number:** 5R35NS097211-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David H Gutmann
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $686,252
- **Award type:** 5
- **Project period:** 2016-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062526

## Citation

> US National Institutes of Health, RePORTER application 10062526, Defining the Mechanistic Basis for Neurofibromatosis-1 Nervous System Disease Heterogeneity (5R35NS097211-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10062526. Licensed CC0.

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