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Kinetochore Specification and Function

Award Number: R01GM074215
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: 05/01/2005
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Kinetochore Specification and Function - PROJECT SUMMARY For the development of an organism from a single cell, the genome must be duplicated and precisely distributed during every cell division. Given the astronomical number of cell division events involved in building and maintaining organisms (by one estimate, the adult human body is made up of 40 trillion cells, with at least a couple of trillion dividing every day), it becomes critical that the distribution of the replicated genome to daughter cells, a process known as chromosome segregation, occurs with extremely high accuracy. Errors in chromosome segregation underlie birth defects/infertility and are sufficient to trigger the genomic havoc that is a hallmark of cancer. Thus, understanding the mechanisms by which cells ensure accurate chromosome segregation during cell division has both fundamental and therapeutic significance. Our work is focused on kinetochores, protein machines that assemble on mitotic chromosomes to orchestrate their segregation. Kinetochores coordinate multiple microtubule-interfacing activities that collectively orient and segregate chromosomes, while also integrating mechanical events with signaling mechanisms that control the decision to either remain in or exit from mitosis. Our early work identified a conserved set of proteins, referred to as the KMN network (for Knl1 complex, Mis12 complex, Ndc80 complex) that lies at the heart of these coordinated kinetochore functions. In Aim 1, we focus on the ability of kinetochores to both accelerate and delay exit from mitosis, which we propose optimizes mitotic duration to allow sufficient time for all chromosomes to connect to the spindle, while also minimizing time spent in a vulnerable phase when major cellular functions such as transcription, translation and secretion are downregulated. The work we propose tackles major open questions related to this duality of mitotic timing control by kinetochores. The primary mechanical activity of the kinetochore is to couple to dynamic spindle microtubules. Several distinct microtubule-interfacing activities concentrate at kinetochores as well as on mitotic chromatin, which makes analysis of chromosome-microtubule interactions challenging in a cellular context. In Aim 2, we describe a blank slate–add back approach, in which we eliminate all microtubule-interfacing activities on mitotic chromosomes and then add them back in isolation. This approach complements traditional loss-of-function analysis and will be used to study the microtubule-interfacing activities at kinetochores that orient and center chromosomes on the spindle and that shut of the signal that prevents mitotic exit until microtubule attachments are made. Finally, to achieve accurate segregation, kinetochore-microtubule interactions must be tightly regulated. In Aim 3, we focus on the poorly understood regulatory mechanism by which a spindle pole-generated gradient of the mitotic kinase Aurora A controls kinetochore-microtubule attachments. As Aurora A is amplified in specific cancer contexts, this effort has the potential to reveal cancer-specific dysregulation of chromosome segregation and suggest potential new therapeutic avenues.


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 = $462,237 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	21	4/11/2025	NON-COMPETING CONTINUATION	$462,237
														Subtotal = $462,237

Issue Date FY: 2024 ( Subtotal = $604,031 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	20	3/8/2024	NON-COMPETING CONTINUATION	$416,013
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	20	7/15/2024	NON-COMPETING CONTINUATION	$46,224
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	20	9/9/2024	SUPPLEMENT FOR EXPANSION	$141,794
														Subtotal = $604,031

Issue Date FY: 2023 ( Subtotal = $578,311 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	19	8/23/2023	SUPPLEMENT FOR EXPANSION	$116,074
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	19	3/20/2023	NON-COMPETING CONTINUATION	$462,237
														Subtotal = $578,311

Issue Date FY: 2022 ( Subtotal = $425,424 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	18	4/12/2022	COMPETING CONTINUATION	$425,424
2022	2021	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	003	17	8/2/2022	NON-COMPETING CONTINUATION	$0
2022	2021	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	17	4/4/2022	NON-COMPETING CONTINUATION	$0
2022	2021	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	17	4/4/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $425,424

Issue Date FY: 2021 ( Subtotal = $433,178 )
2021	2021	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	17	2/10/2021	NON-COMPETING CONTINUATION	$392,000
2021	2021	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	17	7/21/2021	SUPPLEMENT FOR EXPANSION	$41,178
														Subtotal = $433,178

Issue Date FY: 2020 ( Subtotal = $392,000 )
2020	2020	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	16	2/25/2020	NON-COMPETING CONTINUATION	$392,000
														Subtotal = $392,000

Issue Date FY: 2019 ( Subtotal = $392,000 )
2019	2019	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	15	3/22/2019	NON-COMPETING CONTINUATION	$392,000
2019	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	13	11/19/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,000

Issue Date FY: 2018 ( Subtotal = $445,629 )
2018	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	14	4/24/2018	COMPETING CONTINUATION	$445,629
														Subtotal = $445,629

Issue Date FY: 2017 ( Subtotal = $376,235 )
2017	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	13	3/8/2017	NON-COMPETING CONTINUATION	$338,611
2017	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	13	3/16/2017	NON-COMPETING CONTINUATION	$0
2017	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	002	13	8/3/2017	NON-COMPETING CONTINUATION	$37,624
														Subtotal = $376,235

Issue Date FY: 2016 ( Subtotal = $376,235 )
2016	2016	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	12	2/3/2016	NON-COMPETING CONTINUATION	$376,235
														Subtotal = $376,235

Issue Date FY: 2015 ( Subtotal = $376,235 )
2015	2015	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	11	2/26/2015	NON-COMPETING CONTINUATION	$376,235
														Subtotal = $376,235

Issue Date FY: 2014 ( Subtotal = $376,235 )
2014	2014	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	10	5/16/2014	COMPETING CONTINUATION	$376,235
														Subtotal = $376,235

Issue Date FY: 2013 ( Subtotal = $342,851 )
2013	2013	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	9	6/19/2013	NON-COMPETING CONTINUATION	$23,094
2013	2013	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	9	5/1/2013	NON-COMPETING CONTINUATION	$319,757
														Subtotal = $342,851

Issue Date FY: 2012 ( Subtotal = $355,286 )
2012	2012	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	8	6/7/2012	NON-COMPETING CONTINUATION	$355,286
														Subtotal = $355,286

Issue Date FY: 2011 ( Subtotal = $355,286 )
2011	2011	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	7	6/14/2011	NON-COMPETING CONTINUATION	$355,286
														Subtotal = $355,286

Issue Date FY: 2010 ( Subtotal = $438,625 )
2010	2010	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	000	5	1/28/2010	SUPPLEMENT FOR EXPANSION	$79,750
2010	2010	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	6	4/16/2010	COMPETING CONTINUATION	$358,875
														Subtotal = $438,625

Issue Date FY: 2009 ( Subtotal = $286,114 )
2009	2009	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	4/16/2009	NON-COMPETING CONTINUATION	$286,114
														Subtotal = $286,114

Issue Date FY: 2008 ( Subtotal = $286,114 )
2008	2008	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	4/30/2008	NON-COMPETING CONTINUATION	$286,114
														Subtotal = $286,114

Issue Date FY: 2007 ( Subtotal = $286,114 )
2007	2007	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	5/1/2007	NON-COMPETING CONTINUATION	$286,114
														Subtotal = $286,114

Grand Total All Awards = $8,157,682

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Kinetochore Specification and Function

Award Number: R01GM074215

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: 05/01/2005

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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