Thursday, November 21, 2024 11/21/2024

The Molecular Regulation of Horizontal Basal Cell Activation in the Olfactory Epithelium

Award Number: R01DC017869
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The capacity of the olfactory epithelium (OE) for replenishing the population of olfactory sensory neurons and for regenerating the epithelium after injury depends on the persistence and maintained function of stem cells within that adult tissue. Decline in sensory function in the elderly is accompanied by pathological changes in the OE that emerge because the normally active olfactory stem and progenitor cells, namely globose basal cells (GBCs), become disordered and eventually depleted. In this setting, the reserve stem cells, namely the horizontal basal cells (HBCs), remain dormant despite the neurogenic exhaustion and disappearance of GBCs; in contrast, if the OE is damaged by an olfactotoxin, the HBCs activate and contribute to the repair of the epithelium. A therapeutic strategy that accomplishes controllable activation of HBCs in the setting of an exhausted OE offers possibly the best approach to treating age-related olfactory dysfunction. We have demonstrated that the transcription factor p63 is the master switch that regulates HBC activation – a precipitous decline in p63 levels is necessary and sufficient for activation. Further, signaling by Notch1 maintains p63 levels and restrains activation; we hypothesize that the ligand for Notch1 is Jagged1 expressed by sustentacular cells, since their selective death is sufficient to activate HBCs. We propose 2 Aims in this application to build on previous advances. Aim 1 focuses on Notch signaling and asks how precisely do the complexities of the Notch pathway in the OE regulate HBCs? Additional questions address the other signals that derive from Sus cells to regulate HBCs. Finally, we will extend our studies manipulating Notch signaling in tissue culture to human HBCs. Aim 2 focuses on the activation process following injury and asks how does proteasomal degradation of p63 contribute to the decline in protein levels in mouse and in human HBCs? When completed, we will have achieved a much more thorough understanding of the process by which HBCs are shifted out of dormancy so that they might contribute to epithelial regeneration. That understanding of mechanism in both mouse, where genetic manipulations offer profound analytic power, and in humans will advance our efforts aimed at identifying therapeutic strategies for alleviating olfactory sensory dysfunction, particularly the sensory loss which accompanies aging.


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: 2024 ( Subtotal = $626,021 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	5	5/2/2024	NON-COMPETING CONTINUATION	$62,601
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	5	1/18/2024	NON-COMPETING CONTINUATION	$563,420
														Subtotal = $626,021

Issue Date FY: 2023 ( Subtotal = $626,021 )
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	4	1/18/2023	NON-COMPETING CONTINUATION	$626,021
														Subtotal = $626,021

Issue Date FY: 2022 ( Subtotal = $626,021 )
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	3	4/20/2022	NON-COMPETING CONTINUATION	$62,602
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	3	1/24/2022	NON-COMPETING CONTINUATION	$563,419
														Subtotal = $626,021

Issue Date FY: 2021 ( Subtotal = $668,096 )
2021	2021	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	2	1/22/2021	NON-COMPETING CONTINUATION	$668,096
														Subtotal = $668,096

Issue Date FY: 2020 ( Subtotal = $894,135 )
2020	2020	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	1	2/6/2020	NEW	$670,295
2020	2020	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	1	6/26/2020	SUPPLEMENT FOR EXPANSION	$223,840
														Subtotal = $894,135

Grand Total All Awards = $3,440,294

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The Molecular Regulation of Horizontal Basal Cell Activation in the Olfactory Epithelium

Award Number: R01DC017869

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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