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Multi-scale computational investigation of functions and mechanisms of protein-RNA phase separation.

Award Number: R35GM138243
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/ABSTRACT In recent years there has emerged a striking realization that liquid-liquid phase separation of proteins and nucleic acids is responsible for the formation of various intracellular membraneless organelles. Examples of organelles formed by phase separation are nucleoli and Cajal bodies in the nucleus and stress granules and P granules in the cytoplasm. The phase separation of protein-RNA composites, in particular, is being appreciated for crucial roles of connecting gene regulatory processes with the phenotypic complexity of eukaryotes. Despite the appar- ent biological signi¿cance and extensive experimental efforts, our understanding of the mechanisms which link protein-RNA phase separation with the transcriptional and catalytic processes is still lacking. The fundamental challenges stem from (i) The molecular heterogeneity and conformational ¿exibility of RNA and proteins, which contain low complexity disordered regions (ii) The juxtaposition of molecular and cellular scales (iii) Presence of non-equilibrium effects due to biochemical reactions, ATP driven processes, and irreversible bio-polymer ¿uxes. The current theoretical and computational paradigms often lack optimal spatio-temporal resolution and the right combination of physical insights for confronting the complex experimental data in a comprehensive and integrative manner. Here, I propose using multi-scale computational tools developed in our lab combined in conjunction with data-driven approaches for revealing general mechanistic principles of protein-RNA phase separation and its link with the functional regulatory processes. The proposal consists of three directions. In the ¿rst direction, we focus on hierarchical coarse-graining of proteins and RNA for studying thermodynamic driving forces of liquid-liquid phase separation in in vitro via molecular dynamics techniques. In the second direction, we employ ¿nite-element and reaction-diffusion simulations trained by molecular models and experimental data for studying the connec- tion of liquid-liquid phase separation with transcriptional and catalytic reactions, which is characteristic of in vivo conditions. In the third direction, we assess the impact of protein-RNA phase separation generic gene regulatory networks by using stochastic dynamics simulations. The speci¿c systems chosen for the study are experimen- tally well-characterized RNA binding proteins FUS, TDP-43, Tau, hnrpa1, and hnrpa2. These systems are known for forming liquid protein-RNA condensates under usually regulated conditions and aggregated structures when misregulated, thereby leading to major neurodegenerative diseases. The completion of the proposed research program will elucidate the nature of the protein-RNA phase sepa- ration its link with functional biochemical reactions and provide much-needed insights for developing intervention strategies for halting protein aggregation into diseases inducing cellular bodies.


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 = $341,330 )
2023	2023	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	4	8/23/2023	NON-COMPETING CONTINUATION	$341,330
														Subtotal = $341,330

Issue Date FY: 2022 ( Subtotal = $340,704 )
2022	2022	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	3	8/2/2022	NON-COMPETING CONTINUATION	$340,704
														Subtotal = $340,704

Issue Date FY: 2021 ( Subtotal = $340,102 )
2021	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	2	8/17/2021	NON-COMPETING CONTINUATION	$340,102
														Subtotal = $340,102

Issue Date FY: 2020 ( Subtotal = $339,524 )
2020	2020	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	1	9/14/2020	NEW	$339,524
														Subtotal = $339,524

Grand Total All Awards = $1,361,660

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Multi-scale computational investigation of functions and mechanisms of protein-RNA phase separation.

Award Number: R35GM138243

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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