Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Stroke is a significant cause of adult disability in the US. Early treatment with thrombolytics or mechanical thrombectomy can significantly improve neurological outcomes in patients with acute ischemic stroke. However, following these acute interventions long term recovery care is primarily limited to treatments designed to prevent stroke recurrence, and to rehabilitation therapies. Factors that can influence long term prognosis, include age, stroke severity, infarct location, and comorbidities. Many stroke survivors do not recover full function for normal activities with ~45% of working age adults unable to return to work by 6 to 12 months following stroke. Thus, a major challenge for stroke treatment is the identification of therapeutic strategies that can help restore function and limit long term disability. In studies conducted in previous cycles of this grant we have focused on understanding the pathways affecting acute stroke injury. We demonstrated that during ischemic stroke, tissue plasminogen activator (tPA) acts on the parenchymal side of the neurovascular unit (NVU) to increase blood brain barrier (BBB) permeability and symptomatic intracerebral hemorrhage (sICH). Studies established that tPA cleavage releases an inhibitory domain activating platelet derived growth factor-C (PDGFC) signaling through the PDGF-receptor-α (PDGFRα) in perivascular astrocytes ultimately leading to downstream signaling by vascular endothelial cell growth factor (VEGF) and PKCβ in vascular endothelial cells (ECs) regulating the tight junction complex through occludin phosphorylation. Our long-term goal is to understand the molecular pathways activated during ischemic stroke and to identify interventions that make stroke treatment safer and more effective. In this application we will build on these data and examine the role of the tPA/PDGFRα/VEGF/PKCβ pathway in post-stroke neuroinflammation, and on the downstream recovery pathways. Our central hypothesis is that in ischemic stroke tPA-mediated early events in the NVU control both neuroinflammation and post-stroke recovery of brain function. We will test this hypothesis in three specific aims that will identify the molecular mechanisms of this pathway during early post- stroke neuroinflammation and on the resolution of neuroinflammation during the transition to healing and the restoration of cerebral blood flow to the damaged brain tissue. Together, these studies will elucidate mechanisms by with tPA controls both inflammation and collateral vessel growth and identify potential interventions to promote long term functional recovery.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
