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Origins, properties, and therapeutic potential of cells that repopulate the microglia-depleted adult brain

Award Number: R01NS083801
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract: We discovered microglia in the adult brain are dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R), and identified several CSF1R inhibitors that crossed into the brain, leading to the elimination of most of the microglia. This remarkable phenomenon has been widely replicated and is now a standard in the field to explore microglial function in health and disease, and clinical trials are being conducted/planned as a result. We also found that we could eliminate microglia for as long as we continued treatment, but upon drug withdrawal, repopulation of the microglial tissue occurred rapidly from proliferating cells throughout the brain that formed a new microglial tissue in ~14 days. We found we could use this to “reset” the inflamed microglial tissue after injury or in aging, and promote functional recovery/cognition. In this continuation, we seek to understand the source and properties of these repopulating cells that become microglia, and study how they modulate neuronal gene expression to rejuvenate the aged brain and fully restore long-term potentiation to that of a young animal. In addition, we describe a second slower source of microglial repopulation, that originates in specific brain niches – the rostral migratory stream (RMS) and associated projecting axonal tracts. This “alternative” repopulation is only unmasked by the complete elimination of microglia. These “alternative” cells arise from unknown cells within these brain niches, and eventually can break out from the white matter tracts and fill the cortex/brain. These cells never attain the numbers, morphologies, or gene expression of microglia, but resemble microglia found in the RMS, which have pro-neurogenesis and increased phagocytotic capabilities than other microglia. We will determine the source of these “alternative” cells, and the consequences of filling the brain with them, including if they have any therapeutic potential, in a mouse model of Alzheimer's disease.


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 = $373,512 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/30/2023	NON-COMPETING CONTINUATION	$373,512
														Subtotal = $373,512

Issue Date FY: 2022 ( Subtotal = $373,512 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	1/24/2022	NON-COMPETING CONTINUATION	$336,160
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	3/28/2022	NON-COMPETING CONTINUATION	$37,352
														Subtotal = $373,512

Issue Date FY: 2021 ( Subtotal = $373,512 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	1/27/2021	NON-COMPETING CONTINUATION	$373,512
														Subtotal = $373,512

Issue Date FY: 2020 ( Subtotal = $373,512 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	2/21/2020	NON-COMPETING CONTINUATION	$373,512
														Subtotal = $373,512

Issue Date FY: 2019 ( Subtotal = $373,512 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	6/7/2019	COMPETING CONTINUATION	$70,594
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	1/25/2019	COMPETING CONTINUATION	$373,512
2019	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	6/7/2019	NON-COMPETING CONTINUATION	-$70,594
														Subtotal = $373,512

Issue Date FY: 2018 ( Subtotal = $318,761 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/25/2018	NON-COMPETING CONTINUATION	$31,877
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/18/2018	NON-COMPETING CONTINUATION	$286,884
														Subtotal = $318,761

Issue Date FY: 2017 ( Subtotal = $319,848 )
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/16/2017	NON-COMPETING CONTINUATION	$287,863
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	6/13/2017	NON-COMPETING CONTINUATION	$31,985
														Subtotal = $319,848

Issue Date FY: 2016 ( Subtotal = $320,874 )
2016	2016	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/3/2016	NON-COMPETING CONTINUATION	$32,088
2016	2016	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/12/2016	NON-COMPETING CONTINUATION	$288,786
														Subtotal = $320,874

Issue Date FY: 2015 ( Subtotal = $321,841 )
2015	2015	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/9/2015	NON-COMPETING CONTINUATION	$321,841
														Subtotal = $321,841

Issue Date FY: 2014 ( Subtotal = $322,515 )
2014	2014	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/10/2014	NEW	$322,515
														Subtotal = $322,515

Grand Total All Awards = $3,471,399

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Origins, properties, and therapeutic potential of cells that repopulate the microglia-depleted adult brain

Award Number: R01NS083801

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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