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Deciphering Post-transcriptional Gene Regulatory Networks During Periods of Host-Pathogen Interaction and Innate Immune Activation

Award Number: R35GM119569
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The long-term mission of my lab is to decipher the critical pathways that sense nucleic acids as a danger, and the post-transcriptional gene regulatory components that facilitate the subsequent cellular response - with the goal that such knowledge significantly contributes to our scientific understanding of innate immunity in human health and disease. Research on innate immunity has traditionally focused on understanding the initiating triggers that ultimately modulate the transcriptional expression of a central set of interferons and cytokines. Much less is known about the post-transcriptional gene regulatory layer, which acts to refine innate immune activation at the RNA level – shaping gene expression to allow for a robust but finite host response while simultaneously preventing aberrant or pathogen- associated gene expression. This remains a striking gap in our understanding given that many aspects of host-pathogen interactions have at its core the detection and suppression of foreign nucleic acids, particularly from viruses. RNA-binding proteins (RBPs) can pre-program the sensitivity of cells to immunogenic stimuli, as well as being essential factors in the anti-viral response. Towards these interests, and in line with our outlined goals of the first cycle of our R35 funding period, we made substantial progress in our investigations on: 1)The characterization of essential and immune-relevant RBPs including ELAVL1 and the YTHDF protein family, 2) the discovery of widespread viral-host RBP interactions through our development of VIR-CLASP and characterization of their impact on viral replication, and 3) the identification and characterization of a novel small molecule catalytic inhibitor of the cGAS-STING pathway, given that we also model dynamic post-transcriptional regulation by examining how this primary cytosolic DNA sensor initiates a generalized innate immune response to perceived foreign nucleic acids. Taken together, my laboratory has grown in expertise in RNA/DNA binding protein biochemistry and -omic scale biology aimed directly at characterizing the essential roles of host RBPs and components of the cGAS pathway in conferring innate immunity. For this research renewal, we aim to expand our understanding within our established research program by pursuing the following major biological questions: 1)How do non-canonical cellular RBPs regulate and maintain host gene expression, especially during viral infection? 2)What are the unique host RBP-viral genome interactions that impact replication and virulence of related viruses within different intracellular environments during early infection? 3) What are the novel components that regulate and facilitate a non-canonical cGAS-dependent pathway promoting innate immune transcriptional activation and programmed DNA 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 = $396,250 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	9	6/7/2024	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2023 ( Subtotal = $396,250 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	8	7/24/2023	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2022 ( Subtotal = $494,385 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	7	5/25/2022	SUPPLEMENT FOR EXPANSION	$98,135
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	7	5/18/2022	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $494,385

Issue Date FY: 2021 ( Subtotal = $396,146 )
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	002	6	9/5/2021	COMPETING CONTINUATION	$42,545
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	6	4/21/2021	COMPETING CONTINUATION	$396,146
2021	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	5	9/5/2021	NON-COMPETING CONTINUATION	-$42,545
														Subtotal = $396,146

Issue Date FY: 2020 ( Subtotal = $392,158 )
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	5	5/12/2020	NON-COMPETING CONTINUATION	$392,158
														Subtotal = $392,158

Issue Date FY: 2019 ( Subtotal = $392,158 )
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	4	5/17/2019	NON-COMPETING CONTINUATION	$392,158
														Subtotal = $392,158

Issue Date FY: 2018 ( Subtotal = $392,158 )
2018	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	3	5/17/2018	NON-COMPETING CONTINUATION	$392,158
														Subtotal = $392,158

Issue Date FY: 2017 ( Subtotal = $392,158 )
2017	2017	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	2	5/11/2017	NON-COMPETING CONTINUATION	$352,942
2017	2017	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	2	6/19/2017	NON-COMPETING CONTINUATION	$39,216
														Subtotal = $392,158

Issue Date FY: 2016 ( Subtotal = $384,989 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	1	8/15/2016	NEW	$384,989
														Subtotal = $384,989

Grand Total All Awards = $3,636,652

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Deciphering Post-transcriptional Gene Regulatory Networks During Periods of Host-Pathogen Interaction and Innate Immune Activation

Award Number: R35GM119569

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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