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Identification and confirmation of blood-brain barrier (BBB) permeability of chemical enhancers of nerve growth factor-dependent neurite outgrowth.

Award Number: SC3GM116667
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2016
PERIOD OF PERFORMANCE END DATE: 10/31/2020

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Identification and confirmation of blood-brain barrier (BBB) permeability of chemical enhancers of nerve growth factor-dependent neurite outgrowth. - DESCRIPTION (provided by applicant): Nerve cell death is a gross neuropathologic feature associated with many neurodegenerative diseases. In the case of Alzheimer's disease (AD), deterioration of synaptic connections made by axons and dendritic processes has been linked to the loss of neurotrophic support in the brain centers affected by AD. Several experimental strategies and discovery schemes have been employed as a means to reverse the effects on neuronal architecture but many have not translated into successful therapies. Direct application of nerve growth factor (NGF) has been shown to augment morphological and sometimes functional recovery of degenerating neurons suggesting that a therapeutic approach that enhances the function of neurotrophins could halt or reverse the effects of AD and other neurodegenerative diseases. Our central hypothesis is that small molecules that enhance the activities of neurotrophins are uniquely suited to study the fundamental mechanisms that underlie activity potentiation of neuropeptides by drug-like chemicals in order to identify potentil targets that could lead to development of novel therapeutics for many age-related neurodegenerative diseases. Consequently, we have synthesized and tested Verbenachalcone (VC), a natural product from Verbena litoralis, and several derivatives that promote neurite outgrowth (NOG) in neuronal cell models. In addition, we utilized the dihydrochalcone backbone of VC as a template in a computational model to identify a small molecule B355252 with NGF-dependent NOG promoting activity and neuroprotective properties. Derivatives of the small molecule with improved toxicity profile have been synthesized. However, the SAR studies have not yielded improvements in compound potency. In this project we propose to identify compounds with novel scaffolds different from that of B355252, which synergize with NGF to enhance NOG by implementing a phenotypic image-based screen. In addition, we will develop and validate an in vitro blood- brain permeability assay to test the analogs and hits from the screen for potential to cross the blood-brain barrier and initiate studies on the signaling mechanisms of lead compounds as a prelude for future in vivo compound studies.


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: 2023 ( Subtotal = -$24,035 )
2023	2019	NORTH CAROLINA CENTRAL UNIVERSITY	1801 FAYETTEVILLE ST	DURHAM	NC	27707	DURHAM	USA	Biomedical Research and Research Training	000	4	3/17/2023	NON-COMPETING CONTINUATION	-$24,035
														Subtotal = -$24,035

Issue Date FY: 2021 ( Subtotal = -$548 )
2021	2019	NORTH CAROLINA CENTRAL UNIVERSITY	1801 FAYETTEVILLE ST	DURHAM	NC	27707	DURHAM	USA	Biomedical Research and Research Training	000	4	5/2/2021	NON-COMPETING CONTINUATION	-$548
														Subtotal = -$548

Issue Date FY: 2019 ( Subtotal = $108,000 )
2019	2019	NORTH CAROLINA CENTRAL UNIVERSITY	1801 FAYETTEVILLE ST	DURHAM	NC	27707	DURHAM	USA	Biomedical Research and Research Training	000	4	1/7/2019	NON-COMPETING CONTINUATION	$108,000
														Subtotal = $108,000

Issue Date FY: 2018 ( Subtotal = $108,000 )
2018	2018	NORTH CAROLINA CENTRAL UNIVERSITY	1801 FAYETTEVILLE ST	DURHAM	NC	27707	DURHAM	USA	Biomedical Research and Research Training	000	3	1/18/2018	NON-COMPETING CONTINUATION	$97,200
2018	2018	NORTH CAROLINA CENTRAL UNIVERSITY	1801 FAYETTEVILLE ST	DURHAM	NC	27707	DURHAM	USA	Biomedical Research and Research Training	001	3	5/11/2018	NON-COMPETING CONTINUATION	$10,800
														Subtotal = $108,000

Issue Date FY: 2017 ( Subtotal = $108,000 )
2017	2017	NORTH CAROLINA CENTRAL UNIVERSITY	1801 FAYETTEVILLE ST	DURHAM	NC	27707	DURHAM	USA	Biomedical Research and Research Training	001	2	6/20/2017	NON-COMPETING CONTINUATION	$10,800
2017	2017	NORTH CAROLINA CENTRAL UNIVERSITY	1801 FAYETTEVILLE ST	DURHAM	NC	27707	DURHAM	USA	Biomedical Research and Research Training	000	2	1/20/2017	NON-COMPETING CONTINUATION	$97,200
														Subtotal = $108,000

Issue Date FY: 2016 ( Subtotal = $108,000 )
2016	2016	NORTH CAROLINA CENTRAL UNIVERSITY	P.O. BOX 19713	DURHAM	NC	27707	DURHAM	USA	Biomedical Research and Research Training	000	1	1/28/2016	NEW	$108,000
														Subtotal = $108,000

Grand Total All Awards = $407,416

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Identification and confirmation of blood-brain barrier (BBB) permeability of chemical enhancers of nerve growth factor-dependent neurite outgrowth.

Award Number: SC3GM116667

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2016

PERIOD OF PERFORMANCE END DATE: 10/31/2020

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