Thursday, November 21, 2024 11/21/2024

Integrating Multi-Scale Imaging, Reaction-Diffusion Simulation, and Markov Model Inference to Enhance Predictive Design and Interpretation of Single-Molecule Gene Regulation Experiments

Award Number: R35GM124747
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 Single-cell imaging can quantify intricate spatial and temporal dynamics of gene regulation that underly important biomedical process ranging from bacterial infections to cancer. This gene regulation is subject to complexities and randomness of biological processes, and its observation is further subject to measurement artifacts due to inefficiencies in biochemical labels and distortions in microscope imaging. Yet, despite these complications, preliminary work shows that it is possible to integrate data and computational models to predict gene regulation in myriad environmental and genetic conditions provided that: (1) models must be constrained by informative and reproducible data, (2) models must be rigorously verified to account for biological and technical variations, and (3) models must be systematically explored to quantify uncertainties. The overarching hypothesis of this project is that spatial and temporal fluctuations observed in subcellular dynamics contain unique information that can be unlocked with improved computational methods and model-guided experiments. To test this hypothesis, this project will create a new research platform to be known as the single-cell Graphical Utility to Interpret and Design Experiments. scGUIDE will combine experimental analysis (e.g., image processing and single-particle tracking to extract quantitative data from fluorescence microscopy experiments), spatial stochastic simulation (e.g., reaction-diffusion models to generate realistic videos to mimic cellular experiments), model abstraction and identification (e.g., parameter inference and uncertainty quantification to translate quantitative observations into predictive insight), and experiment design (e.g., statistical methods to pinpoint which specific experimental conditions are most likely to reveal new biological insight). To demonstrate its broad capabilities, scGUIDE will be used to analyze and design single-cell experiments for four different health-related processes. In yeast, the project will examine the coordination between stress-activated MAPK dynamics and Spt-Ada-Gcn5 Acetyltransferase (SAGA) subunits that control chromatin and RNA transcription/transport dynamics, and which have been implicated in carcinoma, skeletal dysplasia, and retinal degeneration. In human cells, the project will examine the spatiotemporal clustering and phosphorylation of RNAP Polymerase II as it engages in single-gene transcription under CDK-inhibitor cancer treatments. In osteosarcoma cells, the project will explore how competition for local tRNA resources affects translation of single-mRNA molecules in different sub-cellular regions and in human and viral contexts. Finally, the project will explore the effects that epigenetic memory and molecular competition have on the multi- generational activation or repression of the pap operon that allows E. coli to establish uropathogenic infections. Each project will build mechanistic and quantitatively predictive models for how spatial and temporal interactions of transcription or translation factors, enzymes, and complex molecular machines combine with environmental influences to regulate expression at the single-gene, single-mRNA, single-cell, and population levels.


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: 2025 ( Subtotal = $0 )
2025	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	8	11/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $334,400 )
2024	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	8	8/19/2024	NON-COMPETING CONTINUATION	$334,400
														Subtotal = $334,400

Issue Date FY: 2023 ( Subtotal = $334,400 )
2023	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	002	7	9/21/2023	NON-COMPETING CONTINUATION	$334,400
2023	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	001	6	4/11/2023	COMPETING CONTINUATION	$48,772
2023	2021	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	5	4/11/2023	NON-COMPETING CONTINUATION	-$48,772
														Subtotal = $334,400

Issue Date FY: 2022 ( Subtotal = $334,400 )
2022	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	6	9/14/2022	COMPETING CONTINUATION	$334,400
														Subtotal = $334,400

Issue Date FY: 2021 ( Subtotal = $322,682 )
2021	2021	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	5	8/11/2021	NON-COMPETING CONTINUATION	$322,682
														Subtotal = $322,682

Issue Date FY: 2020 ( Subtotal = $322,682 )
2020	2020	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	4	8/17/2020	NON-COMPETING CONTINUATION	$322,682
														Subtotal = $322,682

Issue Date FY: 2019 ( Subtotal = $322,682 )
2019	2019	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	3	9/4/2019	NON-COMPETING CONTINUATION	$322,682
														Subtotal = $322,682

Issue Date FY: 2018 ( Subtotal = $322,682 )
2018	2018	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	2	8/30/2018	NON-COMPETING CONTINUATION	$322,682
														Subtotal = $322,682

Issue Date FY: 2017 ( Subtotal = $322,682 )
2017	2017	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	1	9/14/2017	NEW	$322,682
														Subtotal = $322,682

Grand Total All Awards = $2,616,610

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Integrating Multi-Scale Imaging, Reaction-Diffusion Simulation, and Markov Model Inference to Enhance Predictive Design and Interpretation of Single-Molecule Gene Regulation Experiments

Award Number: R35GM124747

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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