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Endothelial complement C3a receptor mediated cerebral injury in a murine stroke model.

Award Number: R01NS138528
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: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Endothelial complement C3a receptor mediated cerebral injury in a murine stroke model. - PROJECT SUM MARY: Stroke is the leading cause of adult disability worldwide. Though Intravenous (IV) tissue plasminogen activator (tPA) improves outcome after stroke, it is limited by secondary injury including hemorrhagic transformation, blood-brain-barrier disruption and edema. Activation of complement C3 plays a key role in stroke pathogenesis, as the C3a anaphylatoxin binds to its receptor to exacerbate acute post-ischemic brain injury. However, the mechanisms underlying this injury remain unclear. This study will for the first time define a crucial link between complement C3a receptor associated inflammation and myeloid cell mediated synaptic dysfunction post-stroke. Our long-term goal is to translate C3aR antagonist therapy to enhance reperfusion therapy in stroke. To realize this goal, a thorough understanding of complement-dependent processes in ischemic brain is essential. Our central hypothesis is that increased endothelial C3a/C3aR signaling worsens post-ischemic BBB dysfunction, inflammation, synaptic loss, and functional impairment. We propose the following aims: Specific Aim 1: To demonstrate that genetic inhibition of endothelial C3aR protects the BBB, abrogates inflammatory myeloid cell infiltration, and confers neuroprotection following stroke. WT and C3aRflox/flox- Cdh5Cre+aged mice following PT/Sham surgery will be assessed for neurological function, BBB integrity, and tissue biochemistry for 3 months. Brain/blood samples will be collected for FACS-analysis of myeloid cell subsets to evaluate tissue infiltration of peripheral immune cells and tissue histology. Specific Aim 2: To demonstrate that endothelial C3aR genetic deletion will protect against the deleterious effects of post-ischemic tPA administration even at delayed time-points. WT and C3aRflox/flox- Cdh5Cre+aged mice following PT surgery concurrent with i.v. tPA administration (administered at 4h,8h,12h,24h) will be assessed for hemorrhage, BBB integrity, edema, neurological function, tissue biochemistry for 3 months. Brain/blood samples will be collected for FACS-analysis as in Aim 1 Specific Aim 3: To demonstrate that C3aR mediates post-ischemic synapse elimination and demonstrate that inhibition of this process improves long-term functional outcome. WT and C3aRflox/flox-Cdh5Cre+aged mice following PT surgery will be assessed for synaptic function using electrophysiology. Brain and blood samples will be collected for FACS and tissue histology analysis of microglia, neurons, synaptic protein and puncta density in the peri-infarct region over varying time intervals. EXPECTED OUTCOMES: We anticipate that complement inhibition will attenuate both the acute neurovascular injury associated with post-ischemic tPA administration as well as long-term neurological dysfunction associated with post-ischemic synapse elimination in aged mice. IMPACT: These studies will provide foundation for future efforts to translate therapies targeting the deleterious aspects complement activation into human stroke patients.


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	2024	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/9/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $853,135 )
2024	2024	DIGNITY HEALTH	350 W THOMAS RD	PHOENIX	AZ	85013	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/15/2024	NEW	$853,135
														Subtotal = $853,135

Grand Total All Awards = $853,135

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Endothelial complement C3a receptor mediated cerebral injury in a murine stroke model.

Award Number: R01NS138528

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: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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