Monday, March 17, 2025 3/17/2025

Salivary gland response to Desert hedgehog signaling as an antidote to damage from therapeutic radiation

Award Number: R01DE031724
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Salivation is a critical physiological activity that aids digestion, maintains oral health, and supports functions such as speech, swallowing and taste sensation. Salivary gland dysfunction results from ageing, diseases such as Sjögren syndrome and from radiotherapy for head and neck cancers. Therapeutic irradiation causes permanent damage to salivary glands, highlighting their poor regenerative ability. One potential obstacle to recovery of salivation may be that damage, particularly during radiation therapy, is inflicted not only on saliva-generating epithelial cells but also on supporting mesenchymal cells. Indeed, preservation or restoration of mesenchymal cell function may constitute an ideal therapeutic target, as an optimized mesenchymal microenvironment may augment the function and regenerative capacity of residual salivary gland epithelial cells and their progenitors. A knowledge of how mesenchymal cells function during homeostasis and contribute to regeneration after injury thus may provide a new approach to activate mechanisms that protect salivary glands and enhance their repair. In many organs the mesenchymal expression of signals that provide regenerative feedback to the epithelium during homeostasis and injury repair is induced by expression of a Hedgehog (Hh) protein signal from the epithelium. Using mouse genetic models, cell lineage tracing, and single-cell transcriptomics, we have discovered that Desert hedgehog (DHH), the least studied of the three mammalian Hh family members, drives an epithelial-mesenchymal feedback (EMF) circuit in the major adult salivary glands, and that activity of this circuit is crucial for salivary gland maintenance and for regeneration after radiation injury. Importantly, although DHH expression in cells of the salivary gland epithelium is essential for regeneration, our findings also highlight a vital role for mesenchymal response to this signal for execution of the regenerative program. Here we propose to elucidate the role of Hh signaling in salivary gland homeostasis and regeneration by characterizing at a single cell level the transcriptomic and epigenetic consequences of EMF circuit activity, and to assess the conservation of DHH-driven EMF circuitry in human salivary glands. With the goal of manipulating Hh pathway activity for protection from or enhancement of tissue repair after radiation injury, we have developed a conformation-specific nanobody against the Hh receptor Patched1 that activates Hh pathway response. This nanobody can be targeted to specific cell and tissue types, thus mitigating potential adverse effects arising from systemic Hh pathway activation. With this agent, we will test the possibility that precise, tissue-targeted activation of the Hh pathway can effectively enhance endogenous reparative mechanisms for salivary gland protection from and restoration after injury from irradiation like that administered in head and neck cancer therapy.


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 = $448,910 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	000	4	1/17/2025	NON-COMPETING CONTINUATION	$448,910
														Subtotal = $448,910

Issue Date FY: 2024 ( Subtotal = $488,813 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	001	3	6/18/2024	NON-COMPETING CONTINUATION	$39,903
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	000	3	1/11/2024	NON-COMPETING CONTINUATION	$448,910
														Subtotal = $488,813

Issue Date FY: 2023 ( Subtotal = $525,703 )
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	000	2	1/12/2023	NON-COMPETING CONTINUATION	$473,134
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	001	2	2/22/2023	NON-COMPETING CONTINUATION	$52,569
														Subtotal = $525,703

Issue Date FY: 2022 ( Subtotal = $525,703 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	000	1	3/15/2022	NEW	$525,703
														Subtotal = $525,703

Grand Total All Awards = $1,989,129

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Salivary gland response to Desert hedgehog signaling as an antidote to damage from therapeutic radiation

Award Number: R01DE031724

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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