Childhood arterial ischemic stroke: role of TLR4-neutrophil axis in injury and hemorrhagic transformation

Ended Project Grant Awarded Last action

Award ID
R56NS103483
Recipient
Awarding agency
Obligated
$523,382

Award facts

Completion date
Place of performance
San Francisco, CA 94143, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Reperfusion of cerebral microcirculation after cerebral artery blockage can have dual roles - neuroprotection if reperfusion is early but adverse events and increased neurological disability if reperfusion is delayed. Mechanical thrombectomy has revolutionized care in adult stroke and is of proven benefit in multiple randomized clinical trials with time windows gradually increasing from 4.5 to 24 or more hours. In children with arterial ischemic stroke, retrospective case series suggest safety and possible benefit of thrombectomy, however selection bias, lack of non-treated control outcomes and insufficient knowledge of when IT is safe to remove thrombus in childhood arterial ischemic stroke (cais) raise concerns on whether children can safely benefit from endovascular thrombectomy. Knowledge of mechanisms of adverse effects of late recanalization/thrombectomy in cais is essentially inexistent. We will fill this GAP in knowledge using novel cais mice models and explore novel therapeutic agent. Central hypothesis: TLR4-neutrophil axis mediates injury and hemorrhagic transformation in childhood arterial ischemic stroke (cais). In a model of late reperfusion/recanalization in juvenile male and female mice, following 8H transient middle cerebral artery occlusion, we will examine whether pharmacologic neutrophil elastase (NE) inhibition attenuates the magnitude of hemorrhagic transformation, brain edema, injury, the inflammatory response, and alters leukocyte phenotypes. Using multimodality MRI, we will examine effects on secondary hemorrhagic transformation and chronic injury in relation to new vessel formation, vessel complexity in vivo, myelination and long-term functional outcomes. We will examine efficacy of NE inhibition in a model of local thrombus formation in the juvenile brain (aim 1). We will use loss-of-function experiments to determine if disrupted TLR4 signaling in neutrophils attenuates acute hemorrhagic transformation and inflammation and improves long-term functional outcomes of cais (aim 2). We will examine beneficial effects of aptoll, a novel TLR4-binding DNA aptamer shown protective in a IB/IIA acute adult stroke clinical trial, and determine if aptoll protects by disrupting TLR4 signaling in neutrophils and altering neutrophil phenotypes (aim 3). The proposed studies will serve as proof-of-principle in cais models in defining the mechanisms of hemorrhagic transformation following late recanalization or thrombus formation. The proposal is novel conceptually, uses novel animal models and state-of-the art methodologies, and examines if aptoll, the first successful neuroprotectant in humans in a long time, can protect children who suffer stroke and alleviate adverse effects of late recanalization.

Transactions

Action Obligated Date
Amendment $0
Original award $523,382

Subawards

Subrecipient Amount Awarded
Universidad Complutense De Madrid The funding provided for this subcontract will be used to establish a childhood arterial stroke model in postnatal day 21 (P21) mice that consists of local… $48,600

Quick answers

Who received award R56NS103483?

R56NS103483 was awarded to The Regents Of The University Of California. San Francisco by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on April 15, 2018.

How much is award R56NS103483 worth?

$523,382 has been obligated on R56NS103483.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login