Friday, May 9, 2025 5/9/2025

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

Award Number: R35NS097211
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$8,473 )
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/9/2025	NON-COMPETING CONTINUATION	-$8,473
														Subtotal = -$8,473

Issue Date FY: 2024 ( Subtotal = $739,624 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	5/6/2024	NON-COMPETING CONTINUATION	$53,373
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	11/28/2023	NON-COMPETING CONTINUATION	$686,251
														Subtotal = $739,624

Issue Date FY: 2023 ( Subtotal = $762,500 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	11/30/2022	NON-COMPETING CONTINUATION	$762,500
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	4/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $762,500

Issue Date FY: 2022 ( Subtotal = $762,502 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	12/8/2021	SUPPLEMENT FOR EXPANSION	$76,250
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	12/3/2021	NON-COMPETING CONTINUATION	$617,628
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	6/23/2022	NON-COMPETING CONTINUATION	$68,624
														Subtotal = $762,502

Issue Date FY: 2021 ( Subtotal = $686,252 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/13/2020	NON-COMPETING CONTINUATION	$617,628
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/26/2021	NON-COMPETING CONTINUATION	$68,624
														Subtotal = $686,252

Issue Date FY: 2020 ( Subtotal = $686,250 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/17/2020	NON-COMPETING CONTINUATION	$68,623
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/25/2019	NON-COMPETING CONTINUATION	$617,627
														Subtotal = $686,250

Issue Date FY: 2019 ( Subtotal = $686,250 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/16/2018	NON-COMPETING CONTINUATION	$686,250
														Subtotal = $686,250

Issue Date FY: 2018 ( Subtotal = $684,641 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/24/2017	NON-COMPETING CONTINUATION	$616,179
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/25/2018	NON-COMPETING CONTINUATION	$68,462
														Subtotal = $684,641

Issue Date FY: 2017 ( Subtotal = $683,722 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/1/2016	NEW	$683,722
														Subtotal = $683,722

Grand Total All Awards = $5,683,268

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

Award Number: R35NS097211

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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