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Functional roles of genetic risk factors for brain disorders in neurogenesis and neurodevelopment

Award Number: R35NS097370
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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The overarching goal of this program is to define cellular and molecular events during neural development vulnerable to genetic perturbations that increase risk for neurodevelopmental and neurological disorders. Currently, our knowledge of human brain development is largely inferred from animal models, indirect measures of human development, and limited access to human neural tissue. All of these are valid tools to piece together the sequential processes of human neural development but are not sufficient to describe the dynamics with enough temporal or molecular resolution to understand mechanistically how genetic risk factors can affect brain formation and function. Technological advances in cellular reprogramming have now made it possible to derive induced pluripotent stem cells (iPSCs) from adult patients, which are a renewable resource for the generation of human neurons with disease-relevant genetic features. This long-term research program is designed to incorporate human iPSC-based studies with animal models to provide a comprehensive and longitudinal understanding of neural development, from neural stem cell behavior to neuronal development, synapse formation and circuit integration. As a proof-of-principle, these studies will use a prominent copy number variation (CNV) risk factor for multiple neurological disorders, 15q11.2CNVs, to illustrate how multifaceted interrogations of the basic biology of neural development in the context of genetic variation can reveal new targets for testing mechanism-based intervention in relevant subtypes of human neurons, as well as animal models of neural function and behavior. Building on significant scientific discoveries we have made in the fields of stem cell biology, adult neurogenesis, and patient-specific iPSCs, and technological innovations we have developed to meet critical challenges in each of these fields, our primary research focus is to integrate multiple levels of analysis to provide a high-resolution description of the cellular processes and molecular mechanisms of neural development that can be used to probe genetic or environmental risk for neurological disorders. Three interlinked projects will be pursued. Project 1 will focus on adult mouse neurogenesis as a model for neural development and use clonal analysis of neural stem cells and their development, single-cell transcriptome analysis, and transgenic mouse models to dissect molecular, cellular, and circuit level effects of genetic mutations on neural development; Project 2 will use human iPSCs with known genetic risk factors, and targeted differentiation protocols, to interrogate human neural development in 2D and 3D cultures; and Project 3 will focus on identifying the molecular mechanisms and targets of risk genes in both animal models and human iPSC-derived neurons and the rescue of observed deficits through rational therapeutic intervention. This is an opportune moment to synthesize recently developed technologies and build a novel translational platform to study underlying mechanisms of neurological disorders, and facilitate the identification of strategies to diagnose, treat, and prevent the often debilitating consequences of dysregulated neural development.


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: 2024 ( Subtotal = $797,625 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	11/10/2023	NON-COMPETING CONTINUATION	$797,625
														Subtotal = $797,625

Issue Date FY: 2023 ( Subtotal = $886,250 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	12/8/2022	NON-COMPETING CONTINUATION	$886,250
														Subtotal = $886,250

Issue Date FY: 2022 ( Subtotal = $886,250 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	12/3/2021	NON-COMPETING CONTINUATION	$724,500
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	8/16/2022	SUPPLEMENT FOR EXPANSION	$81,250
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	6/23/2022	NON-COMPETING CONTINUATION	$80,500
														Subtotal = $886,250

Issue Date FY: 2021 ( Subtotal = $805,000 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/25/2020	NON-COMPETING CONTINUATION	$724,500
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/1/2021	NON-COMPETING CONTINUATION	$80,500
														Subtotal = $805,000

Issue Date FY: 2020 ( Subtotal = $805,000 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/10/2020	NON-COMPETING CONTINUATION	$80,500
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/4/2019	NON-COMPETING CONTINUATION	$724,500
														Subtotal = $805,000

Issue Date FY: 2019 ( Subtotal = $805,000 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/14/2018	NON-COMPETING CONTINUATION	$805,000
														Subtotal = $805,000

Issue Date FY: 2018 ( Subtotal = $805,000 )
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/21/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$724,500
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	3/16/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$747,149
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	4/30/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$80,500
2018	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	3/16/2018	NEW	-$747,149
														Subtotal = $805,000

Issue Date FY: 2017 ( Subtotal = $816,043 )
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/29/2016	NEW	$816,043
														Subtotal = $816,043

Grand Total All Awards = $6,606,168

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Functional roles of genetic risk factors for brain disorders in neurogenesis and neurodevelopment

Award Number: R35NS097370

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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