Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Elucidating the Mechanism in the Regulation of RNA-binding Protein Phase Separation

Award Number: R35GM138109
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: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2031

Group Awards By:

View Award Description

Elucidating the Mechanism in the Regulation of RNA-binding Protein Phase Separation - Project Summary/Abstract: Liquid–liquid phase separation (LLPS) of RNA-binding proteins (RBPs) is a recently appreciated mechanism of intracellular compartmentalization that underpins the biogenesis of a variety of biocondensates. While LLPS of RBPs supports critical cellular functions, its dysregulation has been implicated in neurodegenerative diseases and cancer. Understanding and reversing aberrant phase transitions may reveal new strategies to mitigate these pathologies. In fact, we and others have established that reversing the aberrant phase transition of disease- linked RBPs, such as FUS and TDP-43, using nuclear import receptors (NIRs) or RBP-binding RNAs can mitigate their toxicity. Thus, regulators of protein phase transition could be leveraged to restore biocondensate function and mitigate proteotoxicity. However, several key knowledge gaps regarding the regulation of phase transition must be filled, to lay the foundation to transform our mechanistic insights into such therapeutic strategies. Thus, the long-term goal of my research program is to achieve a mechanistic understanding of the regulatory network of protein phase separation and leverage our understanding of phase regulation to develop strategies to restore healthy protein phase in cells. Our central hypothesis is that biomolecules that interact with RBPs, such as NIR and RNA, are key regulators of their phase transition and that these regulatory networks become overwhelmed in diseases. I seek to elucidate the molecular mechanism of the regulation of protein phase separation, both in health and under stress. During the first period of this award, we focused on defining the rules governing the chaperone activity of the NIR Kapβ2 and Impβ1 against phase separation of NLS-containing RBP FUS and TDP-43. We also defined the RNA sequence space and the mechanism by which RNA regulates FUS phase separation. Our progress has led to key questions that will guide the next phase of this research: (1) We will use Cryo-EM to gain structural insight into how Kapβ2 engages and chaperones novel non-NLS substrates identified in our recent miniTurbo-mass spectrometry study. (2) We will extend the miniTurbo-mass spectrometry method to two other NIRs, to understand how different NIRs regulate differently localized biocondensates in the cells. (3) We will investigate how RNA structures and dynamics contribute to their regulatory function using advanced single-molecule fluorescence-based biophysical methods. These newly developed methods will also be complemented by conventional biochemistry and cell biology tools to interrogate each question rigorously. Our results will significantly contribute to a comprehensive understanding of the regulatory network of LLPS, a fundamental mechanism with wide-ranging roles in cellular processes and implications in numerous diseases. Furthermore, this work will lay the foundation for developing strategies that can enhance the activity of NIRs and RNA-based oligonucleotides in mitigating aberrant phase transition, both of which provide the basis for developing innovative therapeutics to restore the healthy protein phase in 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: 2026 ( Subtotal = $429,000 )
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	6	5/13/2026	COMPETING CONTINUATION	$429,000
														Subtotal = $429,000

Issue Date FY: 2024 ( Subtotal = $390,000 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	5/24/2024	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2023 ( Subtotal = $390,000 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	7/31/2023	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2022 ( Subtotal = $390,000 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	6/27/2022	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2021 ( Subtotal = $590,000 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	6/28/2021	NON-COMPETING CONTINUATION	$390,000
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	001	2	8/23/2021	SUPPLEMENT FOR EXPANSION	$200,000
														Subtotal = $590,000

Issue Date FY: 2020 ( Subtotal = $390,000 )
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	8/24/2020	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $2,579,000

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Elucidating the Mechanism in the Regulation of RNA-binding Protein Phase Separation

Award Number: R35GM138109

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: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer