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Mechanisms of Kinetochore-Microtubule Attachment and Regulation

Award Number: R35GM130365
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: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Mechanisms of Kinetochore-Microtubule Attachment and Regulation - Project Summary The goal of mitotic cell division is to produce two cells from one and to ensure that each daughter cell inherits an exact copy of the original genetic material. When mitosis malfunctions, a common result is aneuploidy, in which cells contain the incorrect number of chromosomes. This impacts human health, since aneuploidy is a leading cause of birth defects and is implicated in cancer initiation and progression. The fidelity of mitosis depends on kinetochores, which are structures built at defined regions of chromosomes called centromeres. Kinetochores have several essential functions, including the following: (1) they connect chromosomes to spindle microtubules, (2) they regulate the strength of these connections, and (3) they ensure that cells do not exit mitosis if chromosomes are incorrectly attached to microtubules (via the spindle assembly checkpoint). Our lab focuses on understanding kinetochores, and specifically how they establish and regulate attachments to microtubules. Our lab also investigates how tumorigenesis results in kinetochore defects, and how these defects lead to cancer cell-specific vulnerabilities that can be exploited for cancer therapies. The first two projects in the proposal aim to uncover the mechanisms cells use to establish and regulate kinetochore-microtubule attachments in human cells. Based on our recent findings, we have generated new hypotheses for how the Aurora family of kinases (i.e., Aurora A, and Aurora B) impact kinetochore-microtubule attachment stability. A significant obstacle that has hindered progress in understanding how kinetochore kinases precisely regulate kinetochore-microtubule attachments is the lack of tools that permit unobtrusive tracking of the dynamics of these kinases and their activities at kinetochores with high spatial and temporal resolution. We have overcome this by developing methods to generate genetically-encoded, fluorescently-tagged, antibody-based probes that can be used to track these phenomena in living cells. We will use this approach to generate phosphorylation “sensors” that recognize active, phosphorylated forms of Aurora A and Aurora B kinases, as well probes directed to their target substate sites at kinetochores. We will use these tools – and generate new ones – to discover how kinetochore kinases regulate kinetochore-microtubule attachment stability throughout mitosis to ensure successful chromosome segregation. A related project will address how kinetochore-microtubule attachment status is communicated to the checkpoint. For this, we will employ our phospho-sensors, super-resolution imaging, and a newly-developed in vitro chromosome capture assay. Finally, we made the recent discovery that hyperactive signaling by the RAS and MAPK pathways over-stimulates kinetochore kinases to induce kinetochore defects and cancer cell-specific vulnerabilities in laboratory-transformed cells and glioblastoma tumor isolates. We aim to identify the targets of MAPK in mitosis and define new roles for RAS/MAPK signaling in dictating cancer vulnerabilities, with the long- term goal of devising strategies to target kinetochore dysregulation in cancer cells for therapeutic intervention.


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 = $408,242 )
2025	2025	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	004	7	2/26/2025	NON-COMPETING CONTINUATION	$408,242
2025	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	6	11/25/2024	COMPETING CONTINUATION	$0
2025	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	002	6	12/16/2024	COMPETING CONTINUATION	$77,829
2025	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	001	5	12/16/2024	NON-COMPETING CONTINUATION	-$60,470
2025	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	003	5	12/16/2024	SUPPLEMENT FOR EXPANSION	-$17,359
														Subtotal = $408,242

Issue Date FY: 2024 ( Subtotal = $453,118 )
2024	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	6	2/9/2024	COMPETING CONTINUATION	$453,118
														Subtotal = $453,118

Issue Date FY: 2023 ( Subtotal = $471,431 )
2023	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	001	5	5/17/2023	SUPPLEMENT FOR EXPANSION	$105,147
2023	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	5	2/7/2023	NON-COMPETING CONTINUATION	$366,284
														Subtotal = $471,431

Issue Date FY: 2022 ( Subtotal = $366,284 )
2022	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	4	2/25/2022	NON-COMPETING CONTINUATION	$329,653
2022	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	001	4	7/20/2022	NON-COMPETING CONTINUATION	$36,631
														Subtotal = $366,284

Issue Date FY: 2021 ( Subtotal = $533,685 )
2021	2021	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	3	2/19/2021	NON-COMPETING CONTINUATION	$366,284
2021	2021	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	001	3	9/14/2021	SUPPLEMENT FOR EXPANSION	$167,401
														Subtotal = $533,685

Issue Date FY: 2020 ( Subtotal = $366,284 )
2020	2020	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	2	2/28/2020	NON-COMPETING CONTINUATION	$366,284
														Subtotal = $366,284

Issue Date FY: 2019 ( Subtotal = $468,399 )
2019	2019	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	1	2/26/2019	NEW	$256,399
2019	2019	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	001	1	7/30/2019	SUPPLEMENT FOR EXPANSION	$212,000
														Subtotal = $468,399

Grand Total All Awards = $3,067,443

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Mechanisms of Kinetochore-Microtubule Attachment and Regulation

Award Number: R35GM130365

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: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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