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The roles of midbody associated mRNAs in regulating cell proliferation and differentiation

Award Number: R01GM143774
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: 09/20/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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The roles of midbody associated mRNAs in regulating cell proliferation and differentiation - Project Summary During mitosis, the mother cell divides by the formation of a cleavage furrow, leaving two daughter cells connected by a thin intercellular bridge. The resolution of this bridge, abscission, leads to the separation of the two daughter cells. During ingression of the cleavage furrow, the central spindle microtubules are compacted to form a structure known as the midbody (MB). It is now well established that MB regulates cytokinesis by recruiting abscission-mediating proteins, such as ESCRT complex, as well as several regulators of abscission checkpoint. Until recently, the MB was thought to be discarded after division by releasing it into extracellular space. However, recently it was shown that MBs accumulate in stem and cancer cells after mitosis has been completed (called MBsomes) and it has been proposed that MBsomes function as novel signalling platforms that regulate cell differentiation and proliferation. Recently we developed a protocol for purification of post- mitotic MBs and completed their proteomic and RNAseq analyses that led to identification of several mRNAs and mRNA-binding proteins that accumulate at the MB. Importantly, MB-enriched mRNAs encode several ESCRT complex subunits, as well as proteins that stimulate cell proliferation. Furthermore, we show that these MB-enriched mRNAs can be transferred to the neighboring cells via post-mitotic MB internalization. Based on all of these findings, we hypothesize that targeting of selected mRNAs to the MB during cytokinesis play a key role in regulating cell abcission and post-mitotic MBsome signaling. Here we propose three specific aims to test this hypothesis. First, we will map and characterize the domain(s) within 3'-UTR that are needed for mRNA targeting during cytokinesis. We will then use candidate approach, as well as proteomic and CRISPR screens, to identify RNA-binding proteins that interact with these 3”-UTR domains and regulate mRNA targeting and localized translation at the MB. Second, we will test the possibility that MB accumulation/translation of ESCRT mRNAs mediates ESCRP complex targeting to the MB. Third, we will test whether MBsome-dependent transfer of specific mRNAs, such as mRNA encoding proliferation regulator CENP-E contribute to MBsome-induced cell proliferation.


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: 2024 ( Subtotal = $558,521 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	3	8/21/2024	SUPPLEMENT FOR EXPANSION	$237,000
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	001	4	8/22/2024	NON-COMPETING CONTINUATION	$321,521
														Subtotal = $558,521

Issue Date FY: 2023 ( Subtotal = $394,759 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	3	9/1/2023	NON-COMPETING CONTINUATION	$321,521
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	001	3	9/5/2023	SUPPLEMENT FOR EXPANSION	$73,238
														Subtotal = $394,759

Issue Date FY: 2022 ( Subtotal = $394,759 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	2	8/24/2022	NON-COMPETING CONTINUATION	$321,521
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	001	2	9/15/2022	SUPPLEMENT FOR EXPANSION	$73,238
														Subtotal = $394,759

Issue Date FY: 2021 ( Subtotal = $335,396 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	1	9/20/2021	NEW	$335,396
														Subtotal = $335,396

Grand Total All Awards = $1,683,435

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The roles of midbody associated mRNAs in regulating cell proliferation and differentiation

Award Number: R01GM143774

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: 09/20/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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