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From one end to the other: dynamics of human translation initiation and its control

Award Number: K99GM144678
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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From one end to the other: dynamics of human translation initiation and its control - Project Summary Protein synthesis begins via a multi-step and highly-regulated process that culminates with a ribosome poised at a start site on a messenger RNA (mRNA). Loss of control is broadly implicated in human disease, including cancers, developmental disorders, neurological diseases, and viral infections. Since translation initiation is rate limiting, an important regulatory strategy involves multi-protein complexes recruited to the opposite end of the mRNA. Recruited regulatory proteins directly enhance or inhibit assembly of the initiation machinery on the mRNA, thereby tuning protein production up or down. Many molecular mechanisms that underlie translation initiation and its long-range control remain unclear. Current paradigms rely on analyses of complexes that are stable for minutes to hours, as the intrinsic dynamics challenge approaches in bulk solutions. Here, I build off my initial postdoctoral research to track the human translation initiation machinery, mRNA, and regulatory complexes as they interact using single-molecule spectroscopy and purified components in vitro, which I complement with structural analyses. In Aim 1 (K99), I focus on how the ribosomal subunits are recruited to and load onto an mRNA, and determine how these landmark initiation events are dictated by mRNA features. In Aim 2 (K99), I examine how the final initiation steps and the transition into active protein synthesis are coordinated and governed by a universally-conserved GTPase, eIF5B. In Aim 3 (R00), I leverage the obtained training and expertise to examine how translation initiation is controlled via the 3’-end of the mRNA by the CCR4-NOT complex, a major regulator with human-health relevance. As my preliminary data demonstrate, my strategy will overcome previous roadblocks to provide a dynamic view of key molecular branchpoints that underlie translation initiation, reveal how they are targeted for control, and may define molecular bases of disease. Aided by strong collaborations and my mentoring team, the proposed research and training plan will provide me with new conceptual and experimental expertise in structural biology and biophysics and enhance my professional development. Together, this proposal will serve as a strong foundation as I transition into independence and continue my investigation of translational control and how it goes awry in human disease.


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 = $0 )
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	3/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $64,356 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	2	9/14/2023	NON-COMPETING CONTINUATION	-$60,644
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	12/16/2022	NON-COMPETING CONTINUATION	$125,000
														Subtotal = $64,356

Issue Date FY: 2022 ( Subtotal = $100,000 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	12/23/2021	NEW	$100,000
														Subtotal = $100,000

Grand Total All Awards = $164,356

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From one end to the other: dynamics of human translation initiation and its control

Award Number: K99GM144678

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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