Thursday, November 21, 2024 11/21/2024

Collaborative Research: DMS/NIGMS 2: Methods for Systematic Analysis of Post-transcriptional Regulation in Single Cells

Award Number: R01GM144967
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Proteins are the drivers of molecular activity in the cell, but we still lack a comprehensive understanding of the mechanisms by which cells regulate protein abundances. A long-standing question has focused specifically on the mechanisms and degree of post-transcriptional regulation, which also determines the degree to which mRNA levels can be used to predict protein abundances. For example, mRNA levels generally correlate with protein abundance across genes, but that mRNA-protein correlations can vary significantly within genes across conditions, due in part to post-transcriptional regulation, such as regulation of protein synthesis and degradation. Post-transcriptional regulation has been analyzed in bulk samples composed of heterogeneous cell types, but it remains largely unexplored in single cells. To enable systematic analysis of post-transcriptional regulation at single-cell resolution, we need a novel analytic framework which 1) accounts for single-cell measurement error and technical bias, which are convolved with the relevant biological signal for both mRNA and protein abundance 2) leverages probabilistic models which pool information across genes in functional groups or account for the determinants contributing to protein abundance, like ribosomal binding proteins 3) models abundance-dependent missing data in single-cell mRNA and protein data and 4) associates observed post-transcriptions regulation with likely regulatory mechanisms. To achieve these goals, we build upon our long-standing collaboration and propose the following aims: Aim 1. To develop methods for inferring post-transcriptional regulation in single cells. These methods will employ hierarchical models which account for similarities between genes with common regulatory mechanisms. We will explicitly model non-ignorable missing data and account for measurement error in the data. Aim 2. To apply and validate the methodology from Aim 1. We will analyze single-cell mRNA and protein measurements from human immune cells and testis with a focus on identifying and validating functionally related genes regulated by common RNA binding proteins. The research will be integrated into the education programs at the PI's institutions, with a particular focus on capstone experiences. Reproducible software implementations for new tools will be developed. RELEVANCE (See instructions): Dysregulation of post-transcriptional regulation is very frequent in human cancers and other diseases, and usually it affects specific subsets of cells. Despite evidence for the importance of post-transcriptional regulation, it is almost completely unexplored at single-cell level. The goal of the proposed research is to develop new methodologies for characterising post-transcriptional regulation in single cells.


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 = $183,530 )
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	4	8/1/2024	NON-COMPETING CONTINUATION	$183,530
														Subtotal = $183,530

Issue Date FY: 2023 ( Subtotal = $198,936 )
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	3	7/31/2023	NON-COMPETING CONTINUATION	$198,936
														Subtotal = $198,936

Issue Date FY: 2022 ( Subtotal = $203,840 )
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	2	9/22/2022	NON-COMPETING CONTINUATION	$203,840
														Subtotal = $203,840

Issue Date FY: 2021 ( Subtotal = $192,447 )
2021	2021	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	1	9/22/2021	NEW	$192,447
														Subtotal = $192,447

Grand Total All Awards = $778,753

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Collaborative Research: DMS/NIGMS 2: Methods for Systematic Analysis of Post-transcriptional Regulation in Single Cells

Award Number: R01GM144967

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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