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Basement membrane self-assembly and structure

Award Number: R01DK036425
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract: Basement membranes (BMs) are extracellular matrices (ECMs) containing laminins, collagen-IV, nidogens and proteoglycans as structural elements. They provide mechanical support for cells and act as signaling platforms. Laminins mediate BM assembly by adhering to cells, by establishing cytoskeletal links through receptors, by polymerizing, and by recruiting the other BM components. These cell-adherent ECMs are essential for tissue growth, differentiation, and maintenance, attributes that depend upon BM molecular architecture and receptor-binding. Diseases of BMs can result from structural changes that adversely affect muscle, peripheral nerve, kidney and other organs. The long-term goal of the grant is to elucidate mechanisms of BM assembly and architecture-dependent functions. This goal is critical for understanding BM disease pathogenesis and for developing therapies for BM defects. We now seek to determine how BMs can be modified to regain lost function in neuromuscular and renal diseases, explore the molecular basis of laminin polymerization, and elucidate architectural properties of BMs that determine functions. Aim I. Mutations ablating the polymerization laminin a2 subunit result in ambulatory muscular dystrophy (LAMA2-MD) with peripheral nerve amyelination. We succeeded in ameliorating the muscle component of a mouse (dy2J) model of polymerization-deficient dystrophy by transgenic muscle expression of a laminin- binding linker-protein called aLNNd. This leads us to evaluate this protein for repair of the peripheral nerve component of the disease. The aim holds potential for development of a therapy by viral somatic gene delivery. Aim II. Proteins conferring polymerization (aLNNd) and dystroglycan (aDG) receptor-binding (miniagrin, mag) to laminins have been used to ameliorate the severe muscle disease resulting from absent laminin-a2 (dy3K mice). The benefit results from modification of compensatory a4 laminin that otherwise neither polymerizes nor binds to aDG. Normal assembly and functions of a4-laminins will be explored, focusing particularly on peripheral nerve myelination. We plan to complete an analysis of transgene muscle expression in the dy3K mouse, and evaluate aLNNd and mag in Lma2-null peripheral nerve to determine if this ameliorates the paresis. The aim is expected to elucidate laminin contributions needed for myelination and contribute to development of a therapy to treat muscle and nerve in LAMA2-MD arising from total loss of the a2 subunit. Aim III. BM-binding proteins can be engineered to alter BM assembly and functions by increasing receptor binding, inducing polymerization, and altering inter-component binding and spacing. We propose to use these unique reagents to determine if the human laminin mutations that cause dystrophies and renal Pierson syndrome are due to failures of laminin polymerization, to map the polymerization residues on laminin LN domain surfaces accompanied by a structural analysis of the polymer node, probe the separate roles of laminin and collagen-IV polymers on cells, and evaluate inter-laminin spacing of the polymer in determining functions.


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 = $357,750 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	38	6/27/2022	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2021 ( Subtotal = $357,750 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	37	6/29/2021	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2020 ( Subtotal = $357,750 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	36	6/24/2020	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2019 ( Subtotal = $357,750 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	35	6/20/2019	NON-COMPETING CONTINUATION	$357,750
2019	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	33	1/30/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $357,750

Issue Date FY: 2018 ( Subtotal = $357,750 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	34	7/6/2018	COMPETING CONTINUATION	$357,750
2018	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	33	7/3/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $357,750

Issue Date FY: 2017 ( Subtotal = $345,825 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	33	6/22/2017	NON-COMPETING CONTINUATION	$34,582
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	33	1/3/2017	NON-COMPETING CONTINUATION	$311,243
														Subtotal = $345,825

Issue Date FY: 2016 ( Subtotal = $345,825 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	32	12/29/2015	EXTENSION WITH OR WITHOUT FUNDS	$311,242
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	32	2/18/2016	EXTENSION WITH OR WITHOUT FUNDS	$34,583
														Subtotal = $345,825

Issue Date FY: 2015 ( Subtotal = $482,579 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	31	2/12/2015	NON-COMPETING CONTINUATION	$34,582
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	31	1/6/2015	NON-COMPETING CONTINUATION	$311,243
2015	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	29	9/22/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$136,754
														Subtotal = $482,579

Issue Date FY: 2014 ( Subtotal = $345,825 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	30	2/24/2014	NON-COMPETING CONTINUATION	$34,582
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	30	1/7/2014	NON-COMPETING CONTINUATION	$311,243
2014	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	28	2/26/2014	COMPETING CONTINUATION	$165,797
2014	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	28	2/24/2014	COMPETING CONTINUATION	$0
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	29	2/26/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$165,797
														Subtotal = $345,825

Issue Date FY: 2013 ( Subtotal = $202,545 )
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	29	8/9/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$202,545
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	29	9/9/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$202,545
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	008	29	2/26/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$165,797
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	28	2/24/2014	COMPETING CONTINUATION	$0
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	28	8/30/2013	COMPETING CONTINUATION	-$140,576
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	007	28	2/26/2014	COMPETING CONTINUATION	$165,797
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	29	8/30/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$202,545
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	28	8/9/2013	COMPETING CONTINUATION	-$198,724
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	28	2/1/2013	COMPETING CONTINUATION	$339,300
														Subtotal = $202,545

Issue Date FY: 2002 ( Subtotal = $255,839 )
2002	2002	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Kidney Diseases, Urology and Hematology Research	000	17	11/29/2001	NON-COMPETING CONTINUATION	$255,839
														Subtotal = $255,839

Issue Date FY: 2001 ( Subtotal = $248,388 )
2001	2001	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Kidney Diseases, Urology and Hematology Research	000	16	12/25/2000	NON-COMPETING CONTINUATION	$248,388
														Subtotal = $248,388

Issue Date FY: 2000 ( Subtotal = $241,154 )
2000	2000	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Kidney Diseases, Urology and Hematology Research	000	15	12/13/1999	NON-COMPETING CONTINUATION	$241,154
														Subtotal = $241,154

Issue Date FY: 1999 ( Subtotal = $234,129 )
1999	1999	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Kidney Diseases, Urology and Hematology Research	000	14	1/6/1999	NON-COMPETING CONTINUATION	$234,129
														Subtotal = $234,129

Issue Date FY: 1998 ( Subtotal = $240,069 )
1998	1998	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Kidney Diseases, Urology and Hematology Research	000	13	12/19/1997	COMPETING CONTINUATION	$240,069
														Subtotal = $240,069

Grand Total All Awards = $4,730,928

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Basement membrane self-assembly and structure

Award Number: R01DK036425

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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