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Next generation gene expression analysis

Award Number: R35GM127089
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Next generation gene expression analysis - Summary Accumulation of misfolded proteins in the endoplasmic reticulum (ER) and subsequent redox imbalance activate the Unfolded Protein Response (UPR) to restore a healthy cellular proteome. Dysregulation of the UPR is key to human diseases, including neurodegeneration and cancer. The UPR involves all components of gene expression control, i.e. transcription, translation, and RNA and protein degradation, that are highly coordinated and follow intricate dynamics. At first, phosphorylation of the translation initiation factor eIF2α suppresses general protein synthesis while activating translation of specific mRNAs that encode transcription factors such as ATF4. Phosphorylation also activates the IRE1 endonuclease that splices and activates the mRNA of the XBP1 transcription factor. XBP1 and ATF4, together with ATF6 and other transcription factors, trigger a second wave of response by transcribing both UPR and apoptosis genes. Further, XBP1 activity is not only controlled by IRE1, but also by SUMOylation and acetylation. IRE1 in turn can also degrade SUMO mRNA, down-regulating this post-translational modification and creating a feedback mechanism of regulation. These processes are accompanied by extensive RNA and protein degradation that remove irreparable molecules, creating a highly interconnected system. Our recent work using time-series transcriptomics and proteomics data as well as statistical modeling showed that during ER stress, mRNAs change in a pulse-like manner, while protein concentrations adjust less rapidly and appear to switch to a new steady state. Given these intricate relationships, I argue that the time is ripe to introduce systems level analyses to studies of the UPR and assess the processes involved in its gene expression regulation in a comprehensive and unbiased way. My laboratory’s expertise in quantitative mass spectrometry, next-generation sequencing, computational analysis, and experiments to evaluate new mechanisms provides the ideal background for such work. In the next five years, we will move analysis of single time points to trajectories of the stress response; we will progress from examination of concentration changes to estimating rates of RNA and protein synthesis and degradation; and we will map the protein position and changes of diverse post-translational modifications to changes in these rates. These efforts will provide valuable resources and statistics tools to the scientific community. They will also inform on regulatory principles during the UPR and support specific new routes of investigation. We are only beginning to understand the differential use and modification of components of the translation machinery, and in the next five years, we will follow up on our recent findings on ribosome modifications, differential stability of ribosome subunits, and alternative splicing of aminoacyl-tRNA synthetases under stress. Further, even well-studied factors such as ATF4 still are incompletely understood in their regulation, and we will test the role of new sequence elements in ATF4 and other genes in their effect on translation. Finally, the robustness of genes to variation, e.g. mutation, is central to understanding cellular pathology, and again, our recent work suggests that some genes are robust to variation in some rates, but not others. We will test these hypotheses in targeted studies.


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: 2026 ( Subtotal = $391,980 )
2026	2026	MERRIMACK COLLEGE	315 TURNPIKE ST	NORTH ANDOVER	MA	01845	ESSEX	USA	Biomedical Research and Research Training	002	9	8/31/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$391,980
2026	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	8	8/21/2026	NON-COMPETING CONTINUATION	$0
2026	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	8	5/29/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $391,980

Issue Date FY: 2025 ( Subtotal = $448,916 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	8	5/9/2025	NON-COMPETING CONTINUATION	$448,916
2025	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	7	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $448,916

Issue Date FY: 2024 ( Subtotal = $581,742 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	002	7	5/10/2024	NON-COMPETING CONTINUATION	$449,065
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	003	7	6/13/2024	SUPPLEMENT FOR EXPANSION	$132,677
2024	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	5	5/8/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	6	5/8/2024	COMPETING CONTINUATION	$0
														Subtotal = $581,742

Issue Date FY: 2023 ( Subtotal = $466,202 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	002	5	7/27/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	003	6	8/4/2023	COMPETING CONTINUATION	$449,210
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	5	5/4/2023	SUPPLEMENT FOR EXPANSION	$16,992
2023	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	5	7/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $466,202

Issue Date FY: 2022 ( Subtotal = $407,411 )
2022	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	5	4/19/2022	NON-COMPETING CONTINUATION	$407,411
														Subtotal = $407,411

Issue Date FY: 2021 ( Subtotal = $407,411 )
2021	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	4	4/12/2021	NON-COMPETING CONTINUATION	$407,411
														Subtotal = $407,411

Issue Date FY: 2020 ( Subtotal = $458,986 )
2020	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	3	8/24/2020	SUPPLEMENT FOR EXPANSION	$51,575
2020	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	3	4/29/2020	NON-COMPETING CONTINUATION	$407,411
														Subtotal = $458,986

Issue Date FY: 2019 ( Subtotal = $473,305 )
2019	2019	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	2	8/15/2019	SUPPLEMENT FOR EXPANSION	$65,894
2019	2019	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	2	4/23/2019	NON-COMPETING CONTINUATION	$407,411
														Subtotal = $473,305

Issue Date FY: 2018 ( Subtotal = $407,411 )
2018	2018	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	1	3/2/2018	NEW	$407,411
														Subtotal = $407,411

Grand Total All Awards = $4,043,364

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Next generation gene expression analysis

Award Number: R35GM127089

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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