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Salivary gland ionocyte organization and function during homeostasis, repair, and disease

Award Number: R01DE031044
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/18/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Salivary gland ionocyte organization and function during homeostasis, repair, and disease - The salivary glands are exocrine glands that produce saliva. An adequate supply of saliva is critical to the maintenance of oral tissue. Saliva is composed of a variety of electrolytes and also contains immunoglobulins, proteins, enzymes and mucins, suggesting that saliva has a complex function. An important function of salivary gland ducts is to regulate ion homeostasis[1]. Dysfunction of epithelial ion homeostasis can lead to several human diseases[2, 3]. Our lineage tracing experiments using a tamoxifen inducible FGF10CreERT2:R26- Tomato mouse identified new epithelial populations of the Fgf10 expressing cells in the striated (SD), granular (GCT) and excretory ducts (ED) of submandibular (SMG) and parotid (PG) glands. Importantly Fgf10 lineage tracing shows that until postnatal day 7 (P7) only mesenchymal Fgf10 expressing cells are present, however after P10, Fgf10 expression in the mesenchyme shuts down, while a subset of ductal epithelial cells starts to express Fgf10. Using Fluorescence Activated Cell Sorting (FACS) we isolated both mesenchymal and epithelial populations of Fgf10+ cells and performed RNA sequencing (RNA-seq). Analysis of this RNA- seq data combined with analysis of single cell RNA-Seq (scRNAseq) data from P1 and adult SMGs showed that epithelial Fgf10+ populations overlap with the known duct population marked by Ascl3. Moreover, these epithelial Fgf10+ cells expressed many gene characteristics for an ancient type of ionocyte cell: Bsnd, Foxi1, Foxi2, Asgr1, Stap1, several subunits of the H+- ATPase (V-ATPase) and markers of SLC12A1/2 and Slc9a4 transporters. Most importantly Fgf10+ cells expressed cystic fibrosis transmembrane conductance regulator (Cftr) that plays a key role in exocrine secretion, including in salivary glands. We propose that these epithelial Fgf10+/Ascl3+/Cftr+ cells are specialized duct salivary gland ionocytes. Moreover, using two models of Sjogrens syndrome: the NOD.B10Sn-H2b/J and the thrombospondin-1 null (TSP1-/-) mice, we showed a significant decrease in Fgf10+ expression and the number of ionocytes with disease progression. We also showed that epithelial Fgf10+ cells isolated from the SMG are able to maintain proliferation and growth of progenitor and myoepithelial cells, suggesting an additional role for ionocytes in ductal maintenance. In this application we will determine the role of Fgf10 signaling in SMG regeneration and ionocyte function, define factors that control ionocyte differentiation and determine how chronic inflammation affects ionocyte function. In addition, in collaboration with Dr. Hoffman's group using bulk RNA-seq and scRNA-seq data we will investigate whether salivary glands have one type or several types of ionocytes. Our proposed study will provide a starting platform for future studies of ionocytes in basic biology and clinical research.


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 = $604,177 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	5	5/21/2025	NON-COMPETING CONTINUATION	$604,177
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Oral Diseases and Disorders Research	001	5	6/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $604,177

Issue Date FY: 2024 ( Subtotal = $584,495 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	4	5/23/2024	NON-COMPETING CONTINUATION	$584,495
														Subtotal = $584,495

Issue Date FY: 2023 ( Subtotal = $596,425 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	3	5/25/2023	NON-COMPETING CONTINUATION	$596,425
														Subtotal = $596,425

Issue Date FY: 2022 ( Subtotal = $581,508 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	2	5/25/2022	NON-COMPETING CONTINUATION	$581,508
														Subtotal = $581,508

Issue Date FY: 2021 ( Subtotal = $627,729 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	1	8/18/2021	NEW	$627,729
														Subtotal = $627,729

Grand Total All Awards = $2,994,334

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Salivary gland ionocyte organization and function during homeostasis, repair, and disease

Award Number: R01DE031044

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/18/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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