Sunday, December 22, 2024 12/22/2024

COORDINATE CONTROL OF INDIVIDUAL NEURONAL TRANSCRIPTOMES BY TRANSCRIPTION FACTORS AND RNA BINDING PROTEINS

Award Number: R01NS111055
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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The development and function of individual neurons are defined by their unique transcriptomic properties, but despite recent efforts cataloguing single neuron transcriptomes, there remains a gap in our understanding of the causal mechanisms by which gene regulatory factors specify individual neuronal transcriptomes. In particular, little is known about how factors regulating various layers of gene expression, e.g. transcription factors (TFs) and RNA binding proteins (RBPs), coordinately control the transcriptomes of single neurons. This proposal aims to fill the gap by leveraging unique properties of the nematode Caenorhabditis elegans to mechanistically investigate coordinated transcriptomic regulation of specific model neurons in vivo. The well-described and invariant lineage of the C. elegans nervous system, combined with powerful genetic techniques, will enable detailed dissection of TF-RBP control over neuronal development. Additional tools recently developed and adapted in the lab, including combinatorial CRISPR/Cas9, single-neuron in vivo alternative splicing reporters, and neuron-specific FACS sorting followed by RNA Seq, will reveal mechanisms and consequences of coordinated regulation of single neurons in vivo. The objective of this proposal is to define TF-RBP pairs that genetically interact and combinatorially shape neuron-specific transcriptomes. The hypothesis is that cell-specific combinations of TFs and RBPs converge on specific target networks to define neuronal transcriptomes. This hypothesis is supported by preliminary in vivo data in C. elegans showing that (a) certain TFs and RBPs combinatorially define splicing choices including splicing of the conserved neuronal kinase sad-1 in individual neurons such as the touch-sensing neurons, and (b) neuronal TFs and RBPs genetically interact to affect neuronal function and behavior. The hypothesis will be further tested by the experiments proposed in the following aims: 1) Determine molecular mechanisms by which the neuronal TFs and RBPs we have identified coordinately control sad-1 alternative splicing in touch neurons, 2) Define functional consequences of dysregulated touch neuron transcriptomes when these regulatory factors or their target transcripts are lost, and 3) Systematically identify neuronal TFs and RBPs coordinately controlling neuron fate and function in specific tractable neuronal cell types. The expected outcomes of the proposed work are to determine mechanisms and functional consequences of coordinate TF-RBP control over single neuron transcriptomes. The proposed approach is innovative as it departs from the status quo by examining causal mechanisms and consequences of single-neuron transcriptomic regulation across multiple layers of gene regulation in vivo. It is significant because it is expected to advance the field of single-neuron transcriptomics into causal mechanisms, functional consequences, and coordinated regulation in single neurons in vivo. Ultimately, these findings will inform our understanding of how nervous systems develop and are specified.


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 = $334,195 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	5/30/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$101,838
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/4/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$310,078
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	5	7/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$24,117
2024	2023	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ ST RM 130	DALLAS	TX	75205	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	5/30/2024	NON-COMPETING CONTINUATION	-$101,838
2024	2023	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ LANE	DALLAS	TX	75205	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $334,195

Issue Date FY: 2023 ( Subtotal = $314,468 )
2023	2023	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ LANE	DALLAS	TX	75205	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/1/2023	NON-COMPETING CONTINUATION	$31,447
2023	2023	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ LANE	DALLAS	TX	75205	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/22/2022	NON-COMPETING CONTINUATION	$283,021
														Subtotal = $314,468

Issue Date FY: 2022 ( Subtotal = $314,259 )
2022	2022	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ LANE	DALLAS	TX	75205	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/16/2021	NON-COMPETING CONTINUATION	$282,832
2022	2022	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ LANE	DALLAS	TX	75205	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/28/2022	NON-COMPETING CONTINUATION	$31,427
														Subtotal = $314,259

Issue Date FY: 2021 ( Subtotal = $313,880 )
2021	2021	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ LANE	DALLAS	TX	75205	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/14/2021	NON-COMPETING CONTINUATION	$313,880
														Subtotal = $313,880

Issue Date FY: 2020 ( Subtotal = $314,073 )
2020	2020	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ LANE	DALLAS	TX	75205	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/29/2020	NEW	$314,073
														Subtotal = $314,073

Grand Total All Awards = $1,590,875

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COORDINATE CONTROL OF INDIVIDUAL NEURONAL TRANSCRIPTOMES BY TRANSCRIPTION FACTORS AND RNA BINDING PROTEINS

Award Number: R01NS111055

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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