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Planar cell polarity mechanisms and systems architecture

Award Number: R35GM131914
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Planar cell polarity mechanisms and systems architecture - Planar cell polarity (PCP) signaling controls the polarization of cells within the plane of an epithelium, orienting asymmetric cellular structures, cell divisions and cell migration. Numerous medically important developmental defects and physiological processes in vertebrates are under control of PCP signaling, motivating considerable interest in understanding the fundamental logic and underlying mechanisms controlling PCP. Major advances toward achieving this understanding have come from leveraging of genetic approaches only possible in Drosophila, and the evident conservation of mechanism reinforces the utility of flies as a model system. I propose that the next major leaps in understanding will emerge from continued innovation in genetic approaches and from expanding the reach of these approaches by employing them in cross-disciplinary studies with technologies such as single molecule imaging and advanced biochemistry. In flies, PCP signaling controls the orientation of hairs on the adult cuticle, chirality and orientation of ommatidia in the eye, orientation of cell divisions and related processes in other tissues. Several distinct molecular modules contribute to PCP signaling. The core module acts both to generate molecular asymmetry within cells and to coordinate the direction of polarization between neighboring cells. One or more global directional modules orient core polarization with respect to tissue axes, and distinct effector modules interpret core polarity to direct morphogenetic responses. A key goal has been to understand the fundamental workings of the core PCP module. Proteins in the core module segregate within cells to form distinct complexes on opposite sides of the cell, and form intercellular bridges that signal polarity between cells. The observed behavior of this module, combined with mathematical modeling, indicates that the system likely acts as a bistable switch, breaking symmetry to produce a stable, polarized array. Positive and negative feedback necessarily underlie the function of this module, but the molecular mechanisms generating feedback are as yet unknown. Furthermore, molecular-scale asymmetry in PCP is coupled to the formation of clustering of polarity components into discrete puncta, yet the precise role of clustering in polarization is not known. Our major focus going forward will be the dissection of core PCP mechanisms by developing and employing novel genetic tools and by combining these tools with single molecule imaging and advanced biochemistry to unlock an understanding of PCP signaling that previously applied experimental approaches have so far been unable to achieve. The proposed work will deliver an unprecedented view of both the fundamental logic and the precise molecular mechanisms underlying PCP signaling as well as lay the groundwork for potential therapeutic interventions for PCP related pathologies.


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: 2025 ( Subtotal = $974,917 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	002	7	8/7/2025	NON-COMPETING CONTINUATION	$974,917
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	6	11/5/2024	COMPETING CONTINUATION	$0
2025	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	5	4/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $974,917

Issue Date FY: 2024 ( Subtotal = $974,917 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	6	8/21/2024	COMPETING CONTINUATION	$974,917
														Subtotal = $974,917

Issue Date FY: 2023 ( Subtotal = $979,390 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	5	8/10/2023	NON-COMPETING CONTINUATION	$979,390
														Subtotal = $979,390

Issue Date FY: 2022 ( Subtotal = $979,390 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	8/29/2022	NON-COMPETING CONTINUATION	$979,390
														Subtotal = $979,390

Issue Date FY: 2021 ( Subtotal = $979,390 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	9/1/2021	NON-COMPETING CONTINUATION	$979,390
														Subtotal = $979,390

Issue Date FY: 2020 ( Subtotal = $979,390 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	8/31/2020	NON-COMPETING CONTINUATION	$979,390
														Subtotal = $979,390

Issue Date FY: 2019 ( Subtotal = $602,812 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	9/16/2019	NEW	$602,812
														Subtotal = $602,812

Grand Total All Awards = $6,470,206

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Planar cell polarity mechanisms and systems architecture

Award Number: R35GM131914

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/16/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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