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Molecular mechanisms of axon guidance receptor regulation and signaling

Award Number: R35NS097340
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2016
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Molecular mechanisms of axon guidance receptor regulation and signaling - PROJECT SUMMARY Determining how neurons are correctly specified and assembled into functional circuits will provide insight into developmental disorders of the nervous system and may suggest therapeutic approaches to promote nerve regeneration. Slit and Netrin, and their Robo and Fra/DCC receptors, are evolutionary conserved families of signaling molecules that play important roles in regulating neuronal development; however, the understanding of how these receptors are regulated and how they signal to direct axon growth and guidance is incomplete. These are important questions because perturbations of these signaling pathways are implicated in diseases of nervous system development. Slits, Netrins and their receptors also play essential roles outside of the nervous system and disruptions of these pathways are associated with several kinds of cancer. Our research program focuses on three broad areas related to the roles and regulation of these molecules in neuronal development using the genetically tractable Drosophila embryonic nervous system as a model. First, we are working to define functional and molecular links between conserved transcriptional regulators that impart neuronal subtype identity and the Robo and Fra/DCC receptors that coordinate axon guidance and dendrite morphogenesis in response to Slit and Netrin. Here, we will use genetic and molecular screening approaches, including Fluorescence Activated Cell sorting (FACs) of defined subsets of motor neurons, together with transcript profiling in wild type and mutant backgrounds, to systematically identify additional effectors of these transcriptional programs. Second, we are characterizing a newly discovered mechanism through which the Frazzled/DCC receptor intracellular domain (ICD) itself can act in the nucleus as a transcriptional activator to regulate commissureless expression to ensure that commissural axons avoid premature responses to midline repellent Slit. Here, we will use genetic and molecular approaches to identify factors that cooperate with the Fra ICD to regulate transcription and transcript profiling methods to identify additional targets of the Fra ICD. In addition, we will explore whether signaling from the nucleus is a common property of axon guidance receptors and through collaboration we will test if this is a conserved property of guidance receptors. Third, we are determining the molecular mechanisms underlying Robo and Fra/DCC receptor signaling during axon guidance using molecular, genetic, biochemical and cell biological approaches. Specifically, we use in vivo genetic manipulation, together with fluorescently tagged receptors and reporters of signaling molecule activity in vitro, to define the cell biological outputs of receptor activation with sub-cellular resolution. Our research program will define new concepts in the molecular biology of axon guidance, inform studies of related proteins in mammalian systems and will likely enhance our understanding of neural developmental disorders.


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 = $0 )
2025	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	11/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $858,935 )
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	002	8	6/5/2024	NON-COMPETING CONTINUATION	$0
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	11/9/2023	NON-COMPETING CONTINUATION	$796,950
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	001	8	5/10/2024	NON-COMPETING CONTINUATION	$61,985
														Subtotal = $858,935

Issue Date FY: 2023 ( Subtotal = $885,500 )
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	$885,500
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	001	7	8/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $885,500

Issue Date FY: 2022 ( Subtotal = $885,500 )
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	000	6	12/3/2021	NON-COMPETING CONTINUATION	$579,600
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	12/10/2021	SUPPLEMENT FOR EXPANSION	$241,500
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	8/9/2022	NON-COMPETING CONTINUATION	$64,400
														Subtotal = $885,500

Issue Date FY: 2021 ( Subtotal = $671,980 )
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	1/25/2021	SUPPLEMENT FOR EXPANSION	$27,980
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	12/17/2020	NON-COMPETING CONTINUATION	$579,600
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	002	5	4/5/2021	NON-COMPETING CONTINUATION	$64,400
														Subtotal = $671,980

Issue Date FY: 2020 ( Subtotal = $644,000 )
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	000	4	12/10/2019	NON-COMPETING CONTINUATION	$579,600
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	$64,400
														Subtotal = $644,000

Issue Date FY: 2019 ( Subtotal = $656,497 )
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	1/29/2019	NON-COMPETING CONTINUATION	$638,885
2019	2019	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	3	3/11/2019	SUPPLEMENT FOR EXPANSION	$17,612
														Subtotal = $656,497

Issue Date FY: 2018 ( Subtotal = $638,885 )
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	11/24/2017	NON-COMPETING CONTINUATION	$574,995
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	001	2	4/30/2018	NON-COMPETING CONTINUATION	$63,890
														Subtotal = $638,885

Issue Date FY: 2017 ( Subtotal = $526,536 )
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/6/2016	NEW	$526,536
														Subtotal = $526,536

Grand Total All Awards = $5,767,833

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Molecular mechanisms of axon guidance receptor regulation and signaling

Award Number: R35NS097340

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2016

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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