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[Jang R01AG058560 transfer] Role of BubR1 as a juvenile protective factor in hippocampal aging

Award Number: R01AG058560
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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[Jang R01AG058560 transfer] Role of BubR1 as a juvenile protective factor in hippocampal aging - PROJECT SUMMARY Aging is the most significant negative regulator of hippocampal neurogenesis, contributing to impairments in synaptic plasticity and cognitive function. The main goal of this application is to identify juvenile protective factors (JPFs) that are capable of maintaining neurogenesis and cognitive function in aged mice so that effective therapeutic strategies for age-related cognitive disorders can be realized. Towards identifying novel JPFs, we have recently provided first evidence that the mitotic checkpoint kinase BubR1 is required for maintaining proper early brain development and hippocampal function later in life. Specifically, BubR1 level is particularly high during early development and then declines to an adult level, followed by further decline during the natural aging process. Given that neurogenesis is robust in childhood, but undergoes a progressive decline with aging, such expression pattern of BubR1 correlates with age-dependent declines in neurogenesis. However, whether sustained BubR1 levels have a protective role in the aged brain, and thus suggest a novel JPF that maintains proper neurogenesis and related hippocampal function in aged mice, remains unknown. Therefore, the main objective of this application is to resolve whether sustained high level of BubR1 in aged brain prevents age-related hippocampal dysfunction. To support this idea, our preliminary data demonstrate that BubR1 insufficiency accelerates age-dependent impairments in hippocampal neurogenesis. Importantly, while a high level of BubR1 itself does not have any detrimental effects in young mice, it promotes neurogenesis in aged mice. Based on these findings, our central hypothesis is that reduced BubR1 levels with age contribute to age-dependent declines in hippocampal function, and that sustained high levels of BubR1 promote neurogenesis and improve synaptic plasticity and cognitive function in aged mice. Utilizing multiple approaches including mouse genetics, confocal imaging, electrophysiology, and behavior analysis, Aim 1 will determine a key downstream molecular pathway of BubR1 in regulating neurogenesis. Given the well- established role of Wnt signaling in neurogenesis and aging, we will explore the involvement of the Wnt signaling pathway in neurogenesis in both BubR1 insufficient and aged mice. Subsequently, Aim 2 will test whether a sustained high level of BubR1 can restore hippocampal neurogenesis in aged mice. Lastly, Aim 3 will determine if a sustained high level of BubR1 improves synaptic plasticity and cognitive function in aged mice in a neurogenesis-dependent manner. In summary, our findings will not only reveal the etiology of age- related cognitive disorders, but also provide a framework by which therapeutic interventions may target neurogenic declines during normal brain aging. Considering the prevalence of age-associated cognitive deficits, determining the mechanistic elements improving hippocampal function will hold significant implications for the fields of cognitive aging, neurogenesis, neural plasticity, regenerative medicine, and public health.


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 = $0 )
2025	2022	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	5	6/10/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	5	12/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $345,400 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	5	3/2/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$345,400
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	003	5	4/19/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$263,172
2022	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	002	4	4/19/2022	NON-COMPETING CONTINUATION	-$263,172
2022	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	4	3/9/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $345,400

Issue Date FY: 2021 ( Subtotal = $377,049 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	4	2/5/2021	NON-COMPETING CONTINUATION	$377,049
														Subtotal = $377,049

Issue Date FY: 2020 ( Subtotal = $415,198 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	3	1/31/2020	NON-COMPETING CONTINUATION	$415,198
														Subtotal = $415,198

Issue Date FY: 2019 ( Subtotal = $387,949 )
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	2	5/16/2019	SUPPLEMENT FOR EXPANSION	$38,149
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	2	1/14/2019	NON-COMPETING CONTINUATION	$349,800
														Subtotal = $387,949

Issue Date FY: 2018 ( Subtotal = $747,300 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	002	1	9/5/2018	SUPPLEMENT FOR EXPANSION	$397,500
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	1	3/12/2018	NEW	$325,950
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	1	9/2/2018	NEW	$23,850
														Subtotal = $747,300

Grand Total All Awards = $2,272,896

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[Jang R01AG058560 transfer] Role of BubR1 as a juvenile protective factor in hippocampal aging

Award Number: R01AG058560

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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