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A chemical approach to elucidating the structure-function relationships of chondronitin sulfate glycosaminoglycans

Award Number: R01GM093627
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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¿ DESCRIPTION (provided by applicant): This project will focus on chondroitin sulfate glycosaminoglycans (CS GAGs), a class of polysaccharides that play important roles in development, viral invasion, cancer, and spinal cord injury. CS GAGs display diverse sulfation patterns that are spatiotemporally regulated in vivo. However, efforts to identify functions for specific sulfation motifs have been hampered by the structural complexity of CS and a lack of tools. In this grant, we will combine the power of both organic chemistry and biology to overcome these challenges and identify novel functions for specific motifs in the nervous system. The broad objectives of this program are to: (1) advance a fundamental understanding of the structure-function relationships of CS GAGs, (2) understand the roles of CS GAGs in neuroplasticity and regeneration, and (3) develop new approaches to study and manipulate GAG-mediated biological processes, with the long-term goal of stimulating synaptic plasticity and neuronal repair. In the last granting period, we developed a set of chemical tools to study specific sulfation motifs and discovered that a particular motif, CS-E, inhibits axon regeneration after spinal cord injury. Blocking the CS-E motif using an anti-CS-E antibody stimulated axon regeneration in vivo. Moreover, we found that this same motif repels axons and plays a critical role in neural circuit formation during brain development. An important observation from this work was that the activity of CS-E required its interaction with cell-surface receptors and activation of specific inhibitory signaling pathways in neurons. In the present grant, we will develop new approaches to modulate the interactions of CS-E with neuronal receptors, including the viral-mediated delivery of single-chain anti-CS-E antibodies, small- molecule sulfotransferase inhibitors, and glycopolymer mimetics (Aim 1). We will study how CS-E regulates protein signaling complexes, with a particular focus on semaphorin-3A/neuropilin-1/plexin A (Sema3A/Nrp1/PlxnA) and ephrin/Eph receptor (Efn/Eph) complexes (Aims 2a and 3a). Finally, we will investigate the ability of the agents developed in Aim 1 to promote neuroplasticity in the visual cortex (Aims 2b,c) and axon regeneration after spinal cord injury (Aim 3b). These studies are expected to provide new chemical tools to advance an understanding of GAGs and fundamentally change how CS GAGs are viewed - from being static, passive molecules to ligands that actively regulate important signaling pathways. Finally, if successful, the agents developed in Aim 1 could lead to novel therapeutic strategies for stimulating neuronal plasticity and repair in the case of aging, injury, and disease.


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: 2022 ( Subtotal = -$10,096 )
2022	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	11/6/2021	NON-COMPETING CONTINUATION	-$10,096
														Subtotal = -$10,096

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	5/21/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $519,611 )
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	5/2/2018	NON-COMPETING CONTINUATION	$519,611
														Subtotal = $519,611

Issue Date FY: 2017 ( Subtotal = $519,611 )
2017	2017	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	7	5/23/2017	NON-COMPETING CONTINUATION	$519,611
														Subtotal = $519,611

Issue Date FY: 2016 ( Subtotal = $519,611 )
2016	2016	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	6	5/24/2016	NON-COMPETING CONTINUATION	$519,611
														Subtotal = $519,611

Issue Date FY: 2015 ( Subtotal = $536,298 )
2015	2015	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	002	5	8/31/2015	COMPETING CONTINUATION	$536,298
2015	2013	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	8/27/2015	NON-COMPETING CONTINUATION	$0
2015	2013	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	12/31/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $536,298

Issue Date FY: 2013 ( Subtotal = $287,020 )
2013	2013	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	2/4/2013	NON-COMPETING CONTINUATION	$267,687
2013	2013	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	6/25/2013	NON-COMPETING CONTINUATION	$19,333
														Subtotal = $287,020

Issue Date FY: 2012 ( Subtotal = $393,283 )
2012	2012	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	2/9/2012	NON-COMPETING CONTINUATION	$393,283
														Subtotal = $393,283

Issue Date FY: 2011 ( Subtotal = $393,283 )
2011	2011	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	001	2	8/10/2011	NON-COMPETING CONTINUATION	$35,753
2011	2011	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	2/1/2011	NON-COMPETING CONTINUATION	$357,530
														Subtotal = $393,283

Issue Date FY: 2010 ( Subtotal = $397,255 )
2010	2010	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	3/30/2010	NEW	$397,255
														Subtotal = $397,255

Grand Total All Awards = $3,555,876

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A chemical approach to elucidating the structure-function relationships of chondronitin sulfate glycosaminoglycans

Award Number: R01GM093627

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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