Saturday, November 23, 2024 11/23/2024

Leveraging Next-Generation Directed Evolution Platforms and Chemical Control of Proteostasis to Deliver Robust Biotechnologies and Illuminate Roles of Chaperone Networks in Protein Evolution

Award Number: R35GM136354
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

Directed evolution mimics and accelerates natural evolution in the laboratory in order to create useful new biomolecules and to study evolutionary processes. Although methodologies for directed evolution are well- established in test tubes and in simple organisms like E. coli and yeast, there is still a major challenge. Specifi- cally, novel biomolecules derived from directed evolution campaigns in these platforms often fail to function when transferred to more complex cellular environments, such as that of human cells. To address this critical issue, our laboratory recently pioneered a directed evolution platform that can be used to repeatedly generate massive libraries of mutant biomolecules while continuously selecting and enriching the most functional vari- ants directly in the human cell environment. From a chemical biology perspective, we are also deeply engaged in studying functions of the proteostasis network – a vital and unique aspect of the human cellular environment that ensures proteins are correctly folded, processed and trafficked. We have developed an array of chemical genetic tools to modulate proteostasis, and we are now primed to integrate these tools with our directed evolu- tion platform to both evolve previously inaccessible biomolecule functions and gain a deeper understanding of how cells solve protein folding problems. Altogether, this NIGMS MIRA application seeks to combine two of my laboratory's primary interests: (1) Developing and applying next-generation, human cell-based directed evolution platforms to generate biomole- cules optimized for function in complex cells and (2) Integrating evolution with chemical modulation of proteo- stasis to gain new insights into fundamental principles of proteostasis network function. Here, we propose to integrate these research areas to deliver an array of biomolecules that reliably and robustly perform valuable new functions in the complex human cellular milieu. Examples include G-protein coupled receptors controlled by synthetic regulators for neuroscience applications, systems for incorporation of unnatural amino acids in proteins, and inhibitors of important signaling pathways related to disease. All of these targets have proven ex- ceedingly difficult to reliably evolve in lower organisms or test tubes. Beyond these practical advances, we will also integrate human cell-based directed evolution with proteostasis modulation to gain insights into how the network solves protein folding problems. For example, we will use our capacity to modulate proteostasis to test the hypothesis that chaperones can be used to “turbo-charge” directed evolution campaigns by providing ac- cess to otherwise biophysically unacceptable regions of the mutational landscape. Further, we will pursue an understanding of the roles of chaperones in human protein evolution, a process that is particularly important in the setting of tumorigenesis and in the development of drug resistance in oncogenes. Altogether, our contribu- tions will impact fields ranging from biotechnology and drug development to protein folding biophysics, evolu- tionary biology, and cancer research.


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	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $395,526 )
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	4/15/2024	NON-COMPETING CONTINUATION	$335,788
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	002	5	8/6/2024	NON-COMPETING CONTINUATION	$37,311
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	5	4/16/2024	SUPPLEMENT FOR EXPANSION	$22,427
														Subtotal = $395,526

Issue Date FY: 2023 ( Subtotal = $462,809 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	4/24/2023	NON-COMPETING CONTINUATION	$373,099
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	4	4/25/2023	SUPPLEMENT FOR EXPANSION	$89,710
														Subtotal = $462,809

Issue Date FY: 2022 ( Subtotal = $440,381 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	4/12/2022	NON-COMPETING CONTINUATION	$335,786
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	3	6/22/2022	NON-COMPETING CONTINUATION	$37,313
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	002	3	8/17/2022	SUPPLEMENT FOR EXPANSION	$67,282
														Subtotal = $440,381

Issue Date FY: 2021 ( Subtotal = $458,342 )
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	7/14/2021	SUPPLEMENT FOR EXPANSION	$85,243
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	4/20/2021	NON-COMPETING CONTINUATION	$373,099
														Subtotal = $458,342

Issue Date FY: 2020 ( Subtotal = $373,099 )
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	4/24/2020	NEW	$373,099
														Subtotal = $373,099

Grand Total All Awards = $2,130,157

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Leveraging Next-Generation Directed Evolution Platforms and Chemical Control of Proteostasis to Deliver Robust Biotechnologies and Illuminate Roles of Chaperone Networks in Protein Evolution

Award Number: R35GM136354

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer