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Deciphering Trophic Signaling Programs Governing Peripheral Sensory Nervous System Development

Award Number: R01NS111220
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Deciphering Trophic Signaling Programs Governing Peripheral Sensory Nervous System Development - Experiencing a cool breeze or performing an intricate dance step are both realized through a precisely calibrated somatosensory nervous system. How this calibration occurs during nervous system development represents a long-standing question that is fundamental to understanding how we sense our environment. All sensory neurons in the peripheral nervous system (PNS) are derived from a single pool of neural crest progenitor cells, which rapidly differentiate into molecularly distinct classes of neurons in the dorsal root ganglia (DRG), each sensory neuron class responsible for detecting distinct environmental modalities. It has long been assumed that these neurons are pre-programmed to become either nociceptor or proprioceptor, however, our preliminary experiments suggest that final lineage choices of sensory neurons are made after encountering neurotrophic factors derived from target tissues (i.e. skin or muscle). In this proposal, we seek to define how such factors contribute to a trophic signaling axis that drives cell lineage choices. We define this signaling axis or “trophic rheostat” as a soluble target-derived neurotrophic factor, it’s cognate receptor tyrosine kinase, and a synergistic or antagonistic TNFR family member. Our central premise is that differences in the type and/or levels of target-derived trophic signaling drive sensory neuron progenitors toward one of at least 13 terminal cell fates. Our goal is to define the trophic rheostats responsible for each of these developmental choices. To address this idea, we will first map out all cell types in the developing DRG by single cell mass cytometry, measuring at daily timepoints across embryonic and postnatal development to produce a developmental cell atlas of the PNS (Aim1). To determine the influence of trophic signaling rheostats on the differentiation of these cell types, we will investigate the cross-talk and convergence of cell signaling pathways downstream of neurotrophic factor receptors and TNFR family members in vitro (Aim2), and test how perturbing these signaling pathways in vivo influences PNS development and sensory behavioral phenotypes (Aim3). To address these research aims, we are pioneering a combinatorial approach that leverages our expertise in high dimensional single cell analysis, mouse genetics, and neurotrophic signaling, to decipher the trophic signaling rheostats that govern cell differentiation and development in the PNS. We are well positioned to delineate mechanisms that have eluded the field for years. This work will inform our understanding of the development of sensory neurons, rationalizing treatments for the millions of individuals suffering from pain and movement disorders. The mechanisms delineated in this proposal will have broad implications for our understanding of other modalities including taste, audition, olfaction, and vision.


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 = $485,003 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/17/2024	NON-COMPETING CONTINUATION	$35,002
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/18/2023	NON-COMPETING CONTINUATION	$450,001
														Subtotal = $485,003

Issue Date FY: 2023 ( Subtotal = $505,330 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/22/2022	NON-COMPETING CONTINUATION	$454,798
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/2/2023	NON-COMPETING CONTINUATION	$50,532
														Subtotal = $505,330

Issue Date FY: 2022 ( Subtotal = $511,992 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/3/2021	NON-COMPETING CONTINUATION	$460,793
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/21/2022	NON-COMPETING CONTINUATION	$51,199
														Subtotal = $511,992

Issue Date FY: 2021 ( Subtotal = $591,313 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/18/2020	NON-COMPETING CONTINUATION	$466,789
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	6/23/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	3/2/2021	SUPPLEMENT FOR EXPANSION	$72,659
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/19/2021	NON-COMPETING CONTINUATION	$51,865
														Subtotal = $591,313

Issue Date FY: 2020 ( Subtotal = $526,269 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/16/2019	NEW	$526,269
														Subtotal = $526,269

Grand Total All Awards = $2,619,907

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Deciphering Trophic Signaling Programs Governing Peripheral Sensory Nervous System Development

Award Number: R01NS111220

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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