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Mechanisms controlling tissue morphogenesis, architecture, and the response to mechanical forces in C. elegans.

Award Number: R01GM125091
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The role of the apical extracellular matrix (aECM) as an important mediator of animal development is only just beginning to be recognized and explored, and few studies have used intact systems to examine how the aECM affects the response of cells and tissues to mechanical forces. This knowledge gap limits the understanding of fundamental biological processes, which when misregulated can lead to diverse developmental and adult- onset diseases. Recent studies uncovered mechanical forces acting on epidermal cells adjacent to the devel- oping anterior foregut in C. elegans embryos. These studies also identified highly conserved proteins that are required to mediate the response to this force, including FBN-1, a fibrillin-related aECM protein; MEC-8, a splicing factor that regulates FBN-1; and SYM-3 and SYM-4, candidate RAB-11–associated factors implicated in apical protein trafficking. The principal objectives of this application are to understand how the epidermal aECM is generated and how the aECM facilitates morphogenesis, cell organization, and resistance to mechan- ical stress. These objectives will be met by pursuing three specific aims. Aim 1 will identify and further charac- terize key components of the aECM, including FBN-1, and will determine how the aECM is physically attached to the underlying epidermis. Aim 2 will test the hypothesis that SYM-3 and SYM-4 are RAB-11 cofactors and will determine the molecular functions of these proteins and other conserved trafficking components in the transport of protein cargos to the apical membrane. Aim 3 will extend preliminary studies to understand the mechanisms by which diverse embryonic epithelial cells are organized into a rosette structure that must resist mechanical forces to form a normal foregut lumen. We will test the hypothesis that the aECM, acting with the cytoskeleton and adherens junction proteins, maintains the structural integrity of the rosette, a widespread but little-studied embryonic structure. In addition, these studies will reveal the locations, magnitude, and dynamics of mechanical forces acting at cell–cell and cell–ECM junctions and within the cytoskeletal network during C. elegans embryonic development. This research is significant because it will (1) characterize physical forces in an intact developing system and reveal mechanisms governing how cells and tissues respond to mechanical stress; (2) lead to the discovery of novel aECM components and regulators of apical protein trafficking; (3) pro- vide insights into how diverse epithelial cells underlying the aECM organize into rosette structures and resolve to form lumens; and (4) identify genetic modifiers of a fibrillin-related protein, which are clinically important in Marfan syndrome but have not been previously characterized. This research is innovative because (1) it is based on the discovery of a previously unrecognized biomechanical force in C. elegans embryos; (2) it is the first study to directly visualize mechanical forces in developing C. elegans embryos using FRET-based tension sensors; and (3) the phenotypes under study are generally penetrant only when two or more genes have been inactivated, thereby serving as a model for redundant control mechanisms and complex disease traits.


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 = -$1,787 )
2022	2019	UNIVERSITY OF WYOMING	1000 E UNIVERSITY AVE DEPARTMENT 3434	LARAMIE	WY	82071	ALBANY	USA	Biomedical Research and Research Training	000	3	1/3/2022	NON-COMPETING CONTINUATION	-$1,787
														Subtotal = -$1,787

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	UNIVERSITY OF WYOMING	1000 E UNIVERSITY AVE DEPARTMENT 3434	LARAMIE	WY	82071	ALBANY	USA	Biomedical Research and Research Training	000	3	5/20/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $260,840 )
2019	2019	UNIVERSITY OF WYOMING	1000 E UNIVERSITY AVE DEPARTMENT 3434	LARAMIE	WY	82071	ALBANY	USA	Biomedical Research and Research Training	000	3	5/21/2019	NON-COMPETING CONTINUATION	$260,840
														Subtotal = $260,840

Issue Date FY: 2018 ( Subtotal = $249,468 )
2018	2018	UNIVERSITY OF WYOMING	1000 E UNIVERSITY AVE DEPARTMENT 3434	LARAMIE	WY	82071	ALBANY	USA	Biomedical Research and Research Training	000	2	7/19/2018	NON-COMPETING CONTINUATION	$249,468
														Subtotal = $249,468

Issue Date FY: 2017 ( Subtotal = $265,987 )
2017	2017	UNIVERSITY OF WYOMING	1000 E UNIVERSITY AVE DEPARTMENT 3434	LARAMIE	WY	82071	ALBANY	USA	Biomedical Research and Research Training	000	1	8/30/2017	NEW	$265,987
														Subtotal = $265,987

Grand Total All Awards = $774,508

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Mechanisms controlling tissue morphogenesis, architecture, and the response to mechanical forces in C. elegans.

Award Number: R01GM125091

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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