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Role of Extracellular Matrix Assembly in a Tissue Differentiation Model Probed with a Novel Fibronectin Mutant

Award Number: F30HD097983
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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7. Project Summary The proposed work seeks to use a novel mutation in the extracellular matrix (ECM) protein fibronectin (FN) to study the role of proper ECM assembly in tissue development. The ability of cells to assemble and manipulate the ECM is crucial in tissue development, maintenance, and remodeling. Proper ECM production and function is at the heart of a staggering range of physiologic processes, while dysregulation of the ECM causes and contributes to many diseases. The study of mutations in various ECM components has been instrumental in understanding these proteins' processing, function, and significance in physiology and pathology. The FN matrix specifically is critical in early ECM formation, serving as an essential framework for the development of the ECM and in guiding the incorporation and assembly of other ECM proteins and growth factors into the matrix. Despite its importance, we lack information about how the FN matrix develops and how matrix assembly directs cell and ECM development. This in turn limits our ability to understand normal tissue physiology and to develop treatments for diseases caused by defects in ECM assembly and organization. Our limited understanding is in part due to a lack of naturally occurring FN mutations, as complete knockout of FN expression is lethal to the developing embryo. The recent discovery of a FN point mutation in an individual with disordered skeletal development represents a powerful opportunity to study how this point mutation in FN's assembly domain reduces the amount of ECM (Aim 1) and how reductions in matrix affect cellular behavior (Aim 2). Because FN matrix assembly is the first step in construction of a tissue-appropriate ECM, we hypothesize that perturbations of FN matrix assembly early in a developing tissue will disrupt the organization of the ECM and the cell rearrangements and changes in gene expression that are required for cell differentiation. To test this hypothesis, in aim 1, we will perform an analysis of why fibroblasts with a FN assembly domain mutation form reduced FN and type I collagen matrices. We will assess the ability of mutant FN to bind to other FN molecules, track the secretion and fates of different ECM proteins, and look at the impact of a FN mutation on the assembly of other ECM components. In aim 2, we will study the ability of these mutant stem cells to initiate the early stages of tissue development using a model for chondrogenic differentiation, and investigate the impact of deficiency in different ECM components on this development process. This work will provide novel understanding of the effects of a de novo mutation in human FN on matrix assembly, how ECM assembly directs tissue development and cell differentiation, and how perturbations in ECM assembly can lead to developmental defects and disease. Our characterization of this mutation will also lay the groundwork for thoroughly studying any other FN mutations implicated in human 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: 2024 ( Subtotal = -$18,440 )
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Child Health and Human Development Extramural Research	000	5	12/28/2023	NON-COMPETING CONTINUATION	-$18,440
														Subtotal = -$18,440

Issue Date FY: 2022 ( Subtotal = $43,436 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Child Health and Human Development Extramural Research	000	5	2/3/2022	NON-COMPETING CONTINUATION	$51,036
2022	2020	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Child Health and Human Development Extramural Research	002	2	4/22/2022	NON-COMPETING CONTINUATION	-$7,600
2022	2019	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Child Health and Human Development Extramural Research	001	1	4/22/2022	NEW	$0
														Subtotal = $43,436

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Child Health and Human Development Extramural Research	001	4	2/2/2021	NON-COMPETING CONTINUATION	$516
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Child Health and Human Development Extramural Research	000	4	1/25/2021	NON-COMPETING CONTINUATION	$50,520
														Subtotal = $51,036

Issue Date FY: 2020 ( Subtotal = $50,520 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Child Health and Human Development Extramural Research	003	3	6/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$35,320
2020	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Child Health and Human Development Extramural Research	001	2	2/12/2020	NON-COMPETING CONTINUATION	$504
2020	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Child Health and Human Development Extramural Research	000	2	1/27/2020	NON-COMPETING CONTINUATION	$50,016
2020	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Child Health and Human Development Extramural Research	002	2	6/15/2020	NON-COMPETING CONTINUATION	-$35,320
														Subtotal = $50,520

Issue Date FY: 2019 ( Subtotal = $50,016 )
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Child Health and Human Development Extramural Research	001	1	2/1/2019	NEW	$0
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Child Health and Human Development Extramural Research	000	1	2/1/2019	NEW	$50,016
														Subtotal = $50,016

Grand Total All Awards = $176,568

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Role of Extracellular Matrix Assembly in a Tissue Differentiation Model Probed with a Novel Fibronectin Mutant

Award Number: F30HD097983

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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