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Mechanisms of Wg/Wnt regulation by glypican Dlp

Award Number: R00GM141414
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: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Mechanisms of Wg/Wnt regulation by glypican Dlp - PROJECT SUMMARY Wnt signaling is an evolutionarily conserved pathway that regulates several cellular behaviors such as cell proliferation, survival, differentiation, and migration to promote tissue homeostasis. Of note, the Wg/Wnt signaling pathway is important for tissue patterning and is often deregulated in epithelial cancers. Secreted Wnt ligands are distributed in the extracellular space to promote paracrine and long-range signaling in target cells. These paracrine and long-range functions of Wnts are dependent on extracellular Wnt availability, which in part is dictated by cell-surface glypican, Dally-like protein (Dlp). In this proposal, I will focus on molecular mechanisms that dictate Dlp-mediated regulation of Wnt availability and signaling. Dlp’s role in regulating Wnt signaling has been described as ‘biphasic’: By continual binding and release, Dlp simultaneously promotes long-range signaling and restricts paracrine signaling, ensuring proper ligand availability at both ranges. The Page-McCaw lab established Drosophila germarium, a tissue where oogenesis occurs, as a model to study mechanisms that define Wnt signaling ranges, and identified a novel Dlp/Mmp2 (Matrix Metalloprotease 2) module that modulates paracrine and long-range Wnt signaling in the germarium. Specifically, I found that proteolytic cleavage of Dlp by Mmp2 alters its subcellular localization and function to modulate Wnt availability. Additionally, my preliminary data suggest that Dlp/Mmp2 may regulate Wnt signaling in epithelial tumors to promote tumor growth. In Aim 1, I will investigate the molecular events that occur downstream of proteolytic cleavage of Dlp to modulate Wg/Wnt availability and signaling in the germarium and tumors. The extracellular Wnt distribution is tightly linked with its production and secretion. I found that Dlp can modulate Wg (Wnt-1) production in source cells in the germarium. Wg production in source cells in germaria is tightly regulated and this regulation is crucial for proper oogenesis. Additionally, I found that Dlp interacts with non-ligand proteins (a finding that has not been previously reported) that communicate with intracellular cytoskeletal machinery, potentially to modulate cell adhesion and/or shape. In Aim 2, I will investigate novel mechanisms of how Dlp regulates Wnt ligand production and long-range Wg distribution to facilitate long-range Wg signaling. These investigations will uncover previously unappreciated roles of cell-surface glypicans in regulating Wnt signaling and elucidate novel paradigms of developmental strategies employed in multicellular organisms to maintain tissue homeostasis.


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: 2026 ( Subtotal = $224,101 )
2026	2026	UNIVERSITY OF MASSACHUSETTS LOWELL	220 PAWTUCKET ST STE 400	LOWELL	MA	01854	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	1/14/2026	NON-COMPETING CONTINUATION	$224,101
														Subtotal = $224,101

Issue Date FY: 2025 ( Subtotal = $248,999 )
2025	2025	UNIVERSITY OF MASSACHUSETTS LOWELL	600 SUFFOLK ST STE 450	LOWELL	MA	01854	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	12/23/2024	NON-COMPETING CONTINUATION	$224,100
2025	2025	UNIVERSITY OF MASSACHUSETTS LOWELL	220 PAWTUCKET ST STE 400	LOWELL	MA	01854	MIDDLESEX	USA	Biomedical Research and Research Training	001	4	8/14/2025	NON-COMPETING CONTINUATION	$24,899
														Subtotal = $248,999

Issue Date FY: 2024 ( Subtotal = $280,525 )
2024	2024	UNIVERSITY OF MASSACHUSETTS LOWELL	600 SUFFOLK ST STE 450	LOWELL	MA	01854	MIDDLESEX	USA	Biomedical Research and Research Training	001	3	8/13/2024	EXTENSION WITH OR WITHOUT FUNDS	$31,525
2024	2024	UNIVERSITY OF MASSACHUSETTS	600 SUFFOLK ST STE 212	LOWELL	MA	01854	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	12/19/2023	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $280,525

Grand Total All Awards = $753,625

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Mechanisms of Wg/Wnt regulation by glypican Dlp

Award Number: R00GM141414

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: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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