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Mechanisms of Target-Specific Axon Regeneration

Award Number: K99NS121595
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/15/2021
PERIOD OF PERFORMANCE END DATE: 02/27/2023

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Mechanisms of Target-Specific Axon Regeneration - Project Summary Nerve damage is a common affliction that causes sensory and/or motor deficits. Recovery involves a regenerative process in which damaged axons within a nerve fiber must re-extend to the appropriate target tissues, in a process known as target-specific regeneration. This process often fails in humans, leaving patients with chronic health problems. Improving clinical outcomes requires a better understanding of how target-specific regeneration is regulated. We know that components of the nerve support scaffold can guide axon re-extension along simple paths. However, when axons reach nerve branch points, they require more specific guidance mechanisms to differentiate between multiple paths and select the correct one. We have little understanding of what environmental cues guide these decisions, and how they are appropriately interpreted by regrowing axons. The objective of this proposal is to identify cellular and molecular mechanisms that regulate axon targeting decisions to promote target-specific regeneration. I have established the zebrafish vagus nerve as a model to elucidate mechanisms of target-specific axon regeneration. Regenerating vagus axons select between five nerve branches to robustly re-innervate the correct target tissue, although how they do so is not known. I hypothesize that two non-mutually-exclusive mechanisms regulate target-specific regeneration: 1) chemosensation, in which a regenerating axon can interpret spatially patterned chemical guidance cues in the environment that direct its growth; 2) fasciculation, in which a regenerating axon can recognize undamaged axons that are innervating its intended target and use them as a substrate for directed growth. The three aims of this proposal will comprehensively identify how growing axons interact with their environment at the cell biological and molecular levels during target-specific regeneration. In Aim 1, I will combine a novel single-cell chimera regeneration assay with live imaging and genetic and pharmacological manipulations to establish a conceptual understanding of how in vivo axon-environment interactions guide targeting decisions. In Aim 2, I will combine a novel method to label and isolate live neurons based on their innervation target with in vivo and in vitro techniques to precisely measure how axons of each of the five innervation target groups interact with other axons, and with chemical signals, in the environment. In Aim 3, I will combine innervation target-specific neuron isolation with RNAseq and mutant analysis for unbiased identification of molecules that regulate target selection in each of the five innervation target groups. This study will greatly enhance our fundamental understanding of how axons reinnervate their target tissues during regeneration, and provide an important knowledge base to develop improved treatments for nerve damage.


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 = -$14,043 )
2024	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/13/2023	NON-COMPETING CONTINUATION	-$14,043
														Subtotal = -$14,043

Issue Date FY: 2023 ( Subtotal = $52,481 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	12/7/2022	NON-COMPETING CONTINUATION	$123,174
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	3	6/6/2023	NON-COMPETING CONTINUATION	$0
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	3	9/26/2023	NON-COMPETING CONTINUATION	-$70,693
2023	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/30/2022	NEW	-$2,958
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	11/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,958
2023	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	1	12/22/2022	NEW	$0
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	2	12/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $52,481

Issue Date FY: 2022 ( Subtotal = $123,174 )
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	1	7/30/2022	NEW	-$56,099
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	6/14/2022	NEW	-$33,538
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/30/2021	NEW	$123,174
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	6/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$89,637
														Subtotal = $123,174

Grand Total All Awards = $161,612

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Mechanisms of Target-Specific Axon Regeneration

Award Number: K99NS121595

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/15/2021

PERIOD OF PERFORMANCE END DATE: 02/27/2023

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