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Mechanisms of non-apoptotic caspase-3 regulation of auditory brainstem development

Award Number: F31DC019548
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 10/18/2022

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Mechanisms of non-apoptotic caspase-3 regulation of auditory brainstem development - PROJECT ABSTRACT Sound localization depends on the development of precise neural circuits in the auditory brainstem. Abnormal circuit assembly can contribute to auditory dysfunction in developmental disorders. However, the molecular mechanisms responsible for correct auditory brainstem circuit development remain largely unknown. Our lab has previously shown that caspase-3 activity is necessary for development of auditory brainstem circuits in the chick embryo. Throughout development, active caspase-3 is seen in axons and dendrites of auditory brainstem neurons in the ascending pathway of auditory information: first in auditory nerve axons; then in axons of their synaptic target, nucleus magnocellularis (NM); and finally in dendrites of NM’s synaptic target, nucleus laminaris (NL). Inhibition of caspase-3 activity when caspase-3 is present in NM axons results in NM axonal targeting errors, even though no apoptotic cell death occurs in the auditory brainstem until after this time period. These data suggest that caspase-3 is responsible for guiding NM axons in a non-apoptotic manner. To determine how caspase-3 influences NM axon guidance, I aimed to identify auditory brainstem caspase-3 substrates. I screened the peptidomes of caspase-3-inhibited and control brainstems for peptides that displayed a biochemical signature of caspase proteolysis (cleavage C-terminal of glutamate or aspartate residues) and that were observed only in control brainstems. The 421 peptides that fulfilled these two criteria hailed from 287 distinct proteins, which were enriched for several functional categories, including cytoskeletal regulatory proteins and RNA-binding proteins. Here I propose several experiments to test how caspase-3 cleavage of these substrate categories brings about correct auditory brainstem circuit development. In Aim 1, I propose to transfect NM with constructs expressing uncleavable forms of caspase-3 substrates involved in cytoskeletal regulation: myotrophin and fascin-1. Because I believe that caspase-3 inhibition causes NM axon targeting defects by preventing caspase-3 control of cytoskeletal regulation, I hypothesize that these uncleavable substrates will replicate axon targeting defects caused by global caspase-3 inhibition. In Aim 2, I will use UV cross-linking followed by orthogonal organic phase separation (OOPS) to purify RNA-bound proteins, protein-bound RNAs, and the remaining proteome and transcriptome from caspase-3-inhibited and control auditory brainstems. I will then use gene co-expression network analysis of these four datasets to probe the effect of caspase-3 proteolysis of RNA-binding proteins on gene expression in the auditory brainstem. These aims will thus clarify the role of caspase-3 with regard to the substrate categories revealed by my preliminary data, contributing to a fuller understanding of how the apoptotic pathway serves non- apoptotic functions during neurodevelopment and plasticity.


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 = -$14,237 )
2023	2022	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Research Related to Deafness and Communication Disorders	001	2	8/30/2023	NON-COMPETING CONTINUATION	-$3,369
2023	2022	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Research Related to Deafness and Communication Disorders	000	2	11/18/2022	NON-COMPETING CONTINUATION	-$10,868
														Subtotal = -$14,237

Issue Date FY: 2022 ( Subtotal = $41,940 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Research Related to Deafness and Communication Disorders	001	2	4/25/2022	NON-COMPETING CONTINUATION	$717
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Research Related to Deafness and Communication Disorders	002	2	5/23/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Research Related to Deafness and Communication Disorders	000	2	3/16/2022	NON-COMPETING CONTINUATION	$41,224
														Subtotal = $41,940

Issue Date FY: 2021 ( Subtotal = $41,224 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Research Related to Deafness and Communication Disorders	000	1	1/13/2021	NEW	$40,708
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Research Related to Deafness and Communication Disorders	003	1	2/18/2021	NEW	$0
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Research Related to Deafness and Communication Disorders	001	1	1/13/2021	NEW	$0
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Research Related to Deafness and Communication Disorders	002	1	2/2/2021	NEW	$516
														Subtotal = $41,224

Grand Total All Awards = $68,927

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Mechanisms of non-apoptotic caspase-3 regulation of auditory brainstem development

Award Number: F31DC019548

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 10/18/2022

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