Wednesday, January 15, 2025 1/15/2025

Enabling synthesis and biological studies of homogeneous heparan sulfate and chondroitin sulfate glyco-polypeptides and proteoglycans

Award Number: R01GM072667
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Proteoglycans (PGs) are ubiquitous on mammalian cell surfaces and in the extracellular matrix. PGs are made up of heparan sulfate or chondroitin sulfate glycosaminoglycan chains covalently attached to the core protein through tetrasaccharide linkers. PGs play important roles in many biological processes. However, due to the heterogeneity of naturally existing PGs, it is extremely challenging to purify well-defined structures to study the structure and activity relationship. Traditionally, the biological functions of PGs are believed to be dictated by the glycosaminoglycan chains attached. Evidence is emerging that the core protein may significantly impact the glycan activities. During the last grant period, homogeneous heparan sulfate and chondroitin sulfate glycopeptides have been synthesized, providing access to these complex molecules for the first time. However, the synthesis required total over 100 chemical steps to complete a glycopeptide with a heparan sulfate chain, which limited the synthetic output. Furthermore, with the current synthetic strategy, some of the common structural features in PGs are not accessible. To overcome these challenges, in this renewal application, the power of the biosynthetic enzymes will be harnessed to greatly expand the capability for PG synthesis. In aim 1, the key enzymes will be produced to generate the tetrasaccharide linkage region with the core peptide, and to extend the glycan chain. Automated synthesis strategy will be developed to further expedite the synthesis. In aim 2, ligation strategies will be established to synthesize glyco poly- peptides with multiple glycan chains. This will provide a powerful tool to extend the poly-peptide backbone, and to probe the hypothesis that the core protein can modulate glycan activities. In aim 3, synthesis of a chondroitin sulfate proteoglycan bikunin like glycoprotein will be completed. Bikunin is an approved drug to treat the potentially life-threatening sepsis conditions, and its mechanism is currently unclear. Aided by the structurally well-defined synthetic bikunin, the molecular mechanisms of the anti-inflammatory activities of bikunin will be established, demonstrating the power of synthesis in expanding the understanding of the interesting biological properties of these complex molecules.


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 = $290,733 )
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	17	6/5/2024	NON-COMPETING CONTINUATION	$29,074
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	17	11/21/2023	NON-COMPETING CONTINUATION	$261,659
														Subtotal = $290,733

Issue Date FY: 2023 ( Subtotal = $302,450 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	16	12/8/2022	NON-COMPETING CONTINUATION	$272,205
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	16	2/14/2023	NON-COMPETING CONTINUATION	$30,245
														Subtotal = $302,450

Issue Date FY: 2022 ( Subtotal = $307,785 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	15	5/16/2022	NON-COMPETING CONTINUATION	$30,779
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	15	12/20/2021	NON-COMPETING CONTINUATION	$277,006
														Subtotal = $307,785

Issue Date FY: 2021 ( Subtotal = $532,523 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	002	14	7/16/2021	SUPPLEMENT FOR EXPANSION	$212,182
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	14	12/28/2020	COMPETING CONTINUATION	$320,341
2021	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	13	7/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $532,523

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	13	2/20/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $255,208 )
2018	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	13	2/8/2018	NON-COMPETING CONTINUATION	$229,686
2018	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	13	5/18/2018	NON-COMPETING CONTINUATION	$25,522
														Subtotal = $255,208

Issue Date FY: 2017 ( Subtotal = $278,907 )
2017	2017	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	12	6/7/2017	NON-COMPETING CONTINUATION	$27,891
2017	2017	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	12	2/16/2017	NON-COMPETING CONTINUATION	$251,016
														Subtotal = $278,907

Issue Date FY: 2016 ( Subtotal = $383,659 )
2016	2016	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	11	7/11/2016	SUPPLEMENT FOR EXPANSION	$103,458
2016	2016	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	11	2/9/2016	NON-COMPETING CONTINUATION	$280,201
														Subtotal = $383,659

Issue Date FY: 2015 ( Subtotal = $342,948 )
2015	2015	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	10	5/5/2015	COMPETING CONTINUATION	$342,948
														Subtotal = $342,948

Issue Date FY: 2013 ( Subtotal = $287,378 )
2013	2013	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	9	5/22/2013	NON-COMPETING CONTINUATION	$287,378
														Subtotal = $287,378

Issue Date FY: 2012 ( Subtotal = $297,801 )
2012	2012	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	8	5/18/2012	NON-COMPETING CONTINUATION	$297,801
														Subtotal = $297,801

Issue Date FY: 2011 ( Subtotal = $297,801 )
2011	2011	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	7	5/23/2011	NON-COMPETING CONTINUATION	$297,801
														Subtotal = $297,801

Issue Date FY: 2010 ( Subtotal = $221,083 )
2010	2010	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	6	5/10/2010	COMPETING CONTINUATION	$221,083
														Subtotal = $221,083

Issue Date FY: 2009 ( Subtotal = $239,605 )
2009	2009	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	5	6/2/2009	NON-COMPETING CONTINUATION	$239,605
														Subtotal = $239,605

Issue Date FY: 2008 ( Subtotal = $239,473 )
2008	2008	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	4	5/14/2008	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$239,473
														Subtotal = $239,473

Issue Date FY: 2007 ( Subtotal = $255,970 )
2007	2007	UNIVERSITY OF TOLEDO	2801 BANCROFT ST	TOLEDO	OH	43606	LUCAS	USA	Biomedical Research and Research Training	000	3	3/2/2007	NON-COMPETING CONTINUATION	$255,970
														Subtotal = $255,970

Issue Date FY: 2006 ( Subtotal = $271,320 )
2006	2006	UNIVERSITY OF TOLEDO	2801 BANCROFT ST	TOLEDO	OH	43606	LUCAS	USA	Biomedical Research and Research Training	000	2	3/10/2006	NON-COMPETING CONTINUATION	$264,384
2006	2006	UNIVERSITY OF TOLEDO	2801 BANCROFT ST	TOLEDO	OH	43606	LUCAS	USA	Biomedical Research and Research Training	001	1	1/16/2006	SUPPLEMENT FOR EXPANSION	$6,936
														Subtotal = $271,320

Issue Date FY: 2005 ( Subtotal = $252,700 )
2005	2005	UNIVERSITY OF TOLEDO	2801 BANCROFT ST	TOLEDO	OH	43606	LUCAS	USA	Biomedical Research and Research Training	000	1	1/24/2005	NEW	$252,700
														Subtotal = $252,700

Grand Total All Awards = $5,057,344

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Enabling synthesis and biological studies of homogeneous heparan sulfate and chondroitin sulfate glyco-polypeptides and proteoglycans

Award Number: R01GM072667

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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