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Molecular Mechanisms Controlling Differentiation and Circuit Formation of Vomeronasal Sensory Neurons

Award Number: R01DC017149
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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SUMMARY The nervous system is composed of thousands of different neuronal cell types. Neuronal identity and connectivity is defined by the expression of specific gene batteries. How neuronal identity is initiated and maintained is central to understand the molecular causes underlying neurodegenerative diseases. Olfactory dysfunctions often occur in aging, metabolic disorders, and numerous neurological disorders, including depression, Parkinson’s disease, multiple sclerosis, schizophrenia and dementia. Understanding what signals control terminal differentiation, expression patterns, plasticity, and homeostasis of olfactory neurons will fill a critical gap in knowledge. Our proposed studies will identify key mechanisms that underlie neuronal identity, axonal targeting and homeostasis of a specialized chemosensory epithelium. Our overall objective will delineate the molecular connections between olfactory deficits and neurological dysfunctions. The vomeronasal organ (VNO) is a specialized olfactory subsystem responsible to detect pheromones. While humans do not have a functional VNO, the human olfactory epithelium shares some characteristics with the VNO. As a model system, the VNO has a simple cellular structure with a small number of stem/progenitor cells that generate new sensory neurons throughout life. We chose to use this simplified model system to study mechanisms that control neurogenesis, neuron differentiation, cellular plasticity and homeostasis across postnatal life. The neuro-epithelium of the VNO is composed of two main classes of neurons that selectively express receptors encoded by two vomeronasal receptor (VR) gene families: V1R and V2R. While both neuronal types originate from a common pool of progenitor cells, V1R and V2R expressing neurons localize to different areas within the VNO and project to different areas of the accessory olfactory bulb. Our central hypothesis states that the transcription factor tfap2e (AP2e) controls basal VSN’s identity, cell composition of the VNO and its connectivity to the brain. We propose that the vomeronasal sensory neurons retain a high level of cellular plasticity that allows them to be reprogrammed even after terminal differentiation. Moreover, we propose that bone morphogenic protein BMP signaling gradients established by BMP affinity to collagen IV (5, 6), in the basement membrane, initiate the basal differentiation program, AP2e expression and maintenance of the basal VSNs genetic identity throughout life. Our innovative approach will exploit state of the art mouse genetics, 2D and 3D imaging, next generation sequencing, chromatin immunoprecipitation (Chip)-seq, bioinformatics and behavioral testing to uncover the mechanisms that define and maintain the identity of chemosensory neurons in postnatal animals. The proposed research is significant as to understand critical gene regulatory networks in a specialized chemo-sensory epithelium and how changes in morphogenic signaling in postnatal animals affect its cellular composition, tissue homeostasis and neuronal connectivity and to identify mechanisms underlying chemosensory decline and neurodegeneration in humans. The findings from our proposed studies may produce therapeutic strategies to improve the human condition. !


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: 2023 ( Subtotal = $347,625 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	000	5	11/18/2022	NON-COMPETING CONTINUATION	$312,863
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	001	5	1/12/2023	NON-COMPETING CONTINUATION	$34,762
														Subtotal = $347,625

Issue Date FY: 2022 ( Subtotal = $346,546 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	000	4	11/29/2021	NON-COMPETING CONTINUATION	$311,891
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	001	4	3/7/2022	NON-COMPETING CONTINUATION	$0
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	002	4	4/19/2022	NON-COMPETING CONTINUATION	$34,655
														Subtotal = $346,546

Issue Date FY: 2021 ( Subtotal = $385,203 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	001	3	1/7/2021	NON-COMPETING CONTINUATION	$38,521
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	000	3	10/27/2020	NON-COMPETING CONTINUATION	$346,682
														Subtotal = $385,203

Issue Date FY: 2020 ( Subtotal = $346,608 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	000	2	11/1/2019	NON-COMPETING CONTINUATION	$311,947
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	001	2	1/15/2020	NON-COMPETING CONTINUATION	$34,661
														Subtotal = $346,608

Issue Date FY: 2019 ( Subtotal = $385,756 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	000	1	12/3/2018	NEW	$327,893
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Research Related to Deafness and Communication Disorders	001	1	12/13/2018	NEW	$57,863
														Subtotal = $385,756

Grand Total All Awards = $1,811,738

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Molecular Mechanisms Controlling Differentiation and Circuit Formation of Vomeronasal Sensory Neurons

Award Number: R01DC017149

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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