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Role of Microglia in Cerebral Small Vessel Disease (CSVD)/Vascular Cognitive Impairment (VCI)

Award Number: R01NS124627
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Role of Microglia in Cerebral Small Vessel Disease (CSVD)/Vascular Cognitive Impairment (VCI) - PROJECT SUMMARY: Microglia, the brain’s resident immune cells, are implicated in the pathophysiology of chronic ischemic cerebral small vessel disease (CSVD) and vascular cognitive impairment (VCI), a clinically important cause of dementia that preferentially affects white matter (WM). Colony stimulating factor 1 receptor (CSF1R) is a key regulator of myeloid lineage cells. Genetic loss of CSF1R blocks the normal population of resident microglia and systemic treatment with CSF1R antagonists such as PLX5622 results in a marked depletion of microglia in the CNS. Here we propose to evaluate the role of microglia and CSF1R signaling in a novel rodent model of CSVD/VCI developed in the laboratory of our colleague Dr. Edith Hamel (McGill University). Mice overexpressing transforming growth factor-beta1 (TGFOE) and fed a high cholesterol diet (HCD) display impaired cerebrovascular reactivity, diffuse leukoencephalopathy, and cognitive dysfunction that resembles human CSVD/VCI. We will first assess effects of TGFOE and HCD on regional and cell type specific gene expression in microglia and other myeloid cells using single cell RNA sequencing. Next we will determine if treatment with PLX5622 influences neurological, neuroimaging, and/or neurovascular outcomes in TGFOE mice (+/-HCD). We will assess longitudinal WM integrity outcomes using state-of- the-art 14 Tesla MRI with diffusion tensor imaging (DTI) and quantitative tractography. We will also use sophisticated assessments of resting-state functional connectivity (optical imaging of intrinsic signals) and neurocognition. Furthermore, we will perform longitudinal 2-photon brain imaging studies to track changes in the cerebrovasculature during critical periods of CSVD/ VCI disease initiation and progression. We will confirm the microglia-specific nature of our findings using an orthogonal genetic approach by crossing TGFOE mice with a Csf1rflox/flox : HexbCreERT2 bigenic line that exhibits stable, microglia-specific knockdown of Csf1r. We will then feed the trigenic TGFOE : Csf1rflox/flox : HexbCreERT2 line HCD and carry out the same comprehensive set of longitudinal parameters described above. We anticipate that both pharmacologic depletion of microglia and genetic deletion of CSF1R signaling specifically in microglia will attenuate WM inflammation and injury and result in improvement in multiple outcome parameters. In aim 3 we will collaborate with our colleagues in Radiology to use a novel CSF1R radioligand to carry out longitudinal positron emission tomography (PET) on TGFOE mice (+/-HCD) at multiple time points during disease initiation and progression. This will provide critical information on temporal and spatial in vivo expression patterns of CSF1R in the context of CSVD/VCI and generate foundational data for a novel biomarker for neuroinflammation that can be readily scaled up from mouse to humans. Overall, this microglia- and CSF1R signaling-targeted, WM-centric approach will provide important mechanistic information on the pathogenesis of ischemic WM injury in CSVD/VCI and elucidate new potential diagnostic and therapeutic approaches.


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 = $588,699 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/19/2025	NON-COMPETING CONTINUATION	$588,699
														Subtotal = $588,699

Issue Date FY: 2024 ( Subtotal = $591,839 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/30/2024	NON-COMPETING CONTINUATION	$591,839
														Subtotal = $591,839

Issue Date FY: 2023 ( Subtotal = $605,304 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/8/2023	NON-COMPETING CONTINUATION	$605,304
														Subtotal = $605,304

Issue Date FY: 2022 ( Subtotal = $644,728 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/8/2022	NEW	$644,728
														Subtotal = $644,728

Grand Total All Awards = $2,430,570

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Role of Microglia in Cerebral Small Vessel Disease (CSVD)/Vascular Cognitive Impairment (VCI)

Award Number: R01NS124627

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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