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Destabilization of axonal mRNAs by KHSRP complexes during axon regeneration

Award Number: R01NS089633
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Destabilization of axonal mRNAs by KHSRP complexes during axon regeneration - SUMMARY This application asks how localized mRNA stability modifies axonal regeneration capacity, focusing on contributions of the RNA binding protein [RBP] KHSRP. The nervous system makes extensive use of post- transcriptional mechanisms to regulate cellular proteomes in response to extracellular stimuli and physiologic environments during development, function, & in response to axonal injury. Since one mRNA can be translated into protein many times over, how long a given mRNA is available for translation impacts the amount of protein generated from that mRNA. Stability of mRNAs is indeed regulated, with interactions with RBPs stabilizing & destabilizing different mRNAs, as well as interactions with microRNAs targeting some targets for degradation. Translation of mRNAs clearly supports axon regeneration, but we have little knowledge for how stability of axonal mRNAs is locally regulated. We have shown that the RBPs HuD (also called ELAVL4) and KHSRP (also called FUBP2, MARTA1, & ZBP2) compete for binding to neuronal mRNAs with AU-rich elements, where HuD interaction stabilizes and KHSRP interaction destabilizes target mRNAs. At the molecular level, this interaction is impacted by an mRNA’s affinity for binding to HuD or KHSRP. Our work over years 01-05 show that loss of KHSRP increases KHSRP target mRNA levels, causes excessive axonal and dendritic growth, impairs memory consolidation in hippocampus & prefrontal cortex, and increases presynaptic activity in prefrontal cortex and hippocampus. KHSRP is expressed into adulthood, and we surprisingly find that axonal KHSRP levels rapidly increase in peripheral nerves after injury. This increase in axonal KHSRP occurs through intra-axonal translation of its encoding mRNA. Our preliminary data indicate that KHSRP knockout mice show accelerated nerve regeneration pointing to axon-intrinsic functions for KHSRP in regeneration. Based on these observations, we hypothesize that axonal KHSRP controls the rates of axon regeneration through regulation of localized mRNA stability. We will test this hypothesis with the following specific aims: 1) Does KHSRP regulate PNS axon regeneration through a neuron intrinsic mechanism? 2) Does increased axonal KHSRP limit axon regeneration by destabilizing axonal mRNAs encoding regeneration-associated proteins? and 3) Does KHSRP’s protein interactome influence its intra-axonal functions? Completion of the studies here will begin to fill this knowledge gap by focusing on RNA-protein interactions initiated in axons that can affect mRNA survival. This will provide the first subcellular analyses of RBP domain-specific RNA regulons and will bring the first systematic assessment for contributions of RNA survival to peripheral nerve regeneration.


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 = $398,944 )
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	7/17/2025	NON-COMPETING CONTINUATION	$398,944
														Subtotal = $398,944

Issue Date FY: 2024 ( Subtotal = $386,976 )
2024	2024	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	7/25/2024	NON-COMPETING CONTINUATION	$386,976
														Subtotal = $386,976

Issue Date FY: 2023 ( Subtotal = $398,944 )
2023	2023	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	7/31/2023	NON-COMPETING CONTINUATION	$398,944
														Subtotal = $398,944

Issue Date FY: 2022 ( Subtotal = $398,944 )
2022	2022	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/14/2022	NON-COMPETING CONTINUATION	$398,944
														Subtotal = $398,944

Issue Date FY: 2021 ( Subtotal = $407,398 )
2021	2021	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/15/2021	COMPETING CONTINUATION	$407,398
2021	2019	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	9/18/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $407,398

Issue Date FY: 2019 ( Subtotal = $404,248 )
2019	2019	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/7/2019	NON-COMPETING CONTINUATION	$404,248
														Subtotal = $404,248

Issue Date FY: 2018 ( Subtotal = $412,148 )
2018	2018	UNIVERSITY OF SOUTH CAROLINA	1400 WHEAT ST	COLUMBIA	SC	29210	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/30/2018	NON-COMPETING CONTINUATION	$412,148
														Subtotal = $412,148

Issue Date FY: 2017 ( Subtotal = $423,922 )
2017	2017	UNIVERSITY OF SOUTH CAROLINA	1400 WHEAT ST	COLUMBIA	SC	29210	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/6/2017	NON-COMPETING CONTINUATION	$423,922
														Subtotal = $423,922

Issue Date FY: 2016 ( Subtotal = $436,110 )
2016	2016	UNIVERSITY OF SOUTH CAROLINA	516 1/2 SOUTH MAIN STREET	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/24/2016	NON-COMPETING CONTINUATION	$436,110
														Subtotal = $436,110

Issue Date FY: 2015 ( Subtotal = $448,789 )
2015	2015	UNIVERSITY OF SOUTH CAROLINA	516 1/2 SOUTH MAIN STREET	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/16/2015	NEW	$448,789
														Subtotal = $448,789

Grand Total All Awards = $4,116,423

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Destabilization of axonal mRNAs by KHSRP complexes during axon regeneration

Award Number: R01NS089633

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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