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None-genetic metabolic heterogeneity and its influence on drug tolerance

Award Number: R35GM133797
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: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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None-genetic metabolic heterogeneity and its influence on drug tolerance - PROJECT SUMMARY Cellular heterogeneity is ubiquitous across all domains of life. Genetically identical cells can display heterogeneous metabolic activities, even when grown in identical environments. In bacteria, metabolic heterogeneity can shape the ensemble growth rate and affect antibiotic tolerance. In higher organisms, metabolic activity is functionally related to tumor activity and drug tolerance. While cellular heterogeneities in mRNA and protein abundance have been extensively studied, many questions remain regarding metabolic heterogeneity. For instance, what determines the size and frequency of metabolic fluctuation? How is metabolic heterogeneity regulated? Can we control metabolic heterogeneity and therefore eliminate drug-tolerant cells? The lack of fundamental understanding about this important topic has severely limited the development of effective treatments for multiple diseases in which a small number of transiently tolerant cells often cause disease recurrence. Over the past few years, the Zhang lab has developed several methods to study metabolite heterogeneity, including metabolite-biosensor- assisted single-cell imaging and metabolite quantification by cell sorting. Our work identified large, non-genetic heterogeneity in fatty acid biosynthesis, and we exploited metabolic heterogeneity for biotechnology applications (i.e. overproduction of chemicals). In this MIRA proposal, we aim to obtain a systematic understanding of bacteria metabolic heterogeneity by using our existing and novel methods for single-cell metabolic analysis. Using Escherichia coli as a model, we will construct a tunable metabolic system that produces a unique fluorescent metabolite with controlled flux and metabolite concentration. Microfluidics-assisted time-lapse fluorescent microscopy will be used to simultaneously quantify the concentrations of this metabolite and its biosynthetic enzyme, the cell growth rate, and the age of single cells. Data analysis combined with modeling will be used to determine the origin, dynamics, and propagation of metabolic heterogeneity. Furthermore, using the native fatty acid catabolic pathway as a model, we will study how transcriptional and allosteric regulations affect metabolic heterogeneity. In addition, we will explore the influence of metabolic heterogeneity on drug tolerance and seek to reduce metabolic heterogeneity and multimodality. This project will reveal novel principles that govern metabolic heterogeneity and provide a quantitative framework to explain various single- cell phenomena. Understanding the regulation of metabolic heterogeneity and its influence on drug tolerance will inform strategies to eliminate heterogeneous variants that are insensitive to drugs, thus providing new treatments for recurrent diseases.


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: 2023 ( Subtotal = $643,036 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	001	5	6/20/2023	NON-COMPETING CONTINUATION	$393,750
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	4	6/16/2023	SUPPLEMENT FOR EXPANSION	$249,286
														Subtotal = $643,036

Issue Date FY: 2022 ( Subtotal = $393,750 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	4	6/13/2022	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2021 ( Subtotal = $393,750 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	3	6/21/2021	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2020 ( Subtotal = $393,750 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	2	6/12/2020	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2019 ( Subtotal = $392,500 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	1	8/14/2019	NEW	$392,500
														Subtotal = $392,500

Grand Total All Awards = $2,216,786

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None-genetic metabolic heterogeneity and its influence on drug tolerance

Award Number: R35GM133797

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: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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