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Modulating Stochastic Gene Expression for Cell-fate Control and Therapeutics

Award Number: R37AI109593
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2014
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Modulating Stochastic Gene Expression for Cell-fate Control and Therapeutics - PROJECT SUMMARY Stochastic fluctuations in gene expression are unavoidable at the single-cell level and affect fate decisions from HIV to embryonic development. Yet, there remain fundamental gaps in our understanding of the mechanisms generating and regulating expression fluctuations in mammalian cells. Addressing this gap in knowledge is critical to therapeutic development in systems where fluctuations and heterogeneity present treatment barriers, such as in HIV, stem-cell therapeutics, and cancer. Our long-term goal is to develop therapeutics that target mechanisms of cellular heterogeneity to overcome barriers to precise control of cell fate. During the past 5 years, our work established mechanistic roles for noise and heterogeneity, demonstrating that noise is a feature, rather than a bug, of biological systems that can be modulated for therapeutic effect. Specifically, we: (i) elucidated a viral transcriptional-feedback circuit that harnesses noise to regulate HIV latency, (ii) found this circuit to be optimized by evolution to function as a viral bet-hedging circuit, (iii) made contributions to cell biology showing that transcriptional fluctuations are, in general, amplified by nuclear export and translation, and, (iv) we discovered a novel post-transcriptional feedback architecture that efficiently suppresses noise to stabilize fate commitment. Most excitingly, and most relevant to this application, we (v) discovered noise- enhancer molecules that appear to substantially improve viral reactivation from latency and have been used by other labs to increase noise in diverse systems (e.g., circadian rhythm). The objective of this renewal is to identify molecular mechanisms of noise modulation in mammalian cell-fate circuits to enable therapeutic control of noise. Based on our findings and extensive preliminary evidence in embryonic stem cells (ESCs), our central hypothesis is that generalized `core' cellular mechanisms exist to tune expression noise and that these mechanisms can be pharmacologically perturbed. Our specific aims build off our unique tool of noise-enhancer molecules and will: (Aim 1) map the molecular mechanistic pathways of noise enhancer molecules to develop a mathematical model predictive of transcriptome-wide noise in mammalian cells; (Aim 2) map the molecular mechanisms of noise-suppressor molecules; and (Aim 3) to quantify relative contributions of stochastic vs. deterministic mechanisms underlying HIV latency in vivo and safety & efficacy of noise-modulating molecules in vivo. The proposed research has broad significance as it will determine core molecular mechanisms regulating expression in disparate fate-specification models, reveal genetic targets of noise enhancement and suppression that can lead to the development of new broad-spectrum noise modulators, and propel clinical translation of noise-modulating molecules. Ultimately, the knowledge gained will guide new therapeutic approaches to overcome barriers to precise cell-fate control across diverse mammalian systems.


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 = $2,386,540 )
2025	2025	AUTONOMOUS THERAPEUTICS INC	11808 AUTH LN	SILVER SPRING	MD	20902	MONTGOMERY	USA	Allergy and Infectious Diseases Research	005	11	4/3/2025	NON-COMPETING CONTINUATION	$1,927,847
2025	2024	AUTONOMOUS THERAPEUTICS INC	11808 AUTH LN	SILVER SPRING	MD	20902	MONTGOMERY	USA	Allergy and Infectious Diseases Research	004	10	3/26/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$66,573
2025	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	9	12/4/2024	NON-COMPETING CONTINUATION	-$447,173
2025	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	003	9	3/26/2025	SUPPLEMENT FOR EXPANSION	-$11,230
2025	2024	AUTONOMOUS THERAPEUTICS INC	11808 AUTH LN	SILVER SPRING	MD	20902	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	10	12/4/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$905,866
2025	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	9	3/26/2025	NON-COMPETING CONTINUATION	-$55,343
														Subtotal = $2,386,540

Issue Date FY: 2024 ( Subtotal = $1,014,080 )
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	9	3/7/2024	SUPPLEMENT FOR EXPANSION	$95,634
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	003	9	9/12/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	9	5/23/2024	NON-COMPETING CONTINUATION	$91,844
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	9	3/5/2024	NON-COMPETING CONTINUATION	$826,602
														Subtotal = $1,014,080

Issue Date FY: 2023 ( Subtotal = $918,446 )
2023	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	8	2/17/2023	NON-COMPETING CONTINUATION	$918,446
														Subtotal = $918,446

Issue Date FY: 2022 ( Subtotal = $1,098,259 )
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	7	3/1/2022	NON-COMPETING CONTINUATION	$918,446
2022	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	6	11/3/2021	COMPETING CONTINUATION	$179,813
														Subtotal = $1,098,259

Issue Date FY: 2021 ( Subtotal = $962,824 )
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	6	7/14/2021	COMPETING CONTINUATION	$0
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	6	3/2/2021	COMPETING CONTINUATION	$962,824
														Subtotal = $962,824

Grand Total All Awards = $6,380,149

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Modulating Stochastic Gene Expression for Cell-fate Control and Therapeutics

Award Number: R37AI109593

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2014

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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