Targeting Endothelial Senescence to Prevent Late-Onset Cerebrovascular Injury After Cancer Therapy
Description: Survival rates for pediatric medulloblastoma have improved significantly with the use of combined chemotherapy (CCT) and cranial radiotherapy (CRT), yet survivors face a markedly elevated risk of late-onset cerebrovascular complications. Clinical follow-up studies reveal increased incidence of cerebral microhemorrhages (CMHs), stroke, and cognitive decline in this population, but the mechanistic links between cancer therapy, vascular injury, and long-term neurocognitive dysfunction remain poorly defined. Emerging evidence implicates cerebrovascular endothelial cell (CMVEC) senescence as a key driver of vascular fragility, blood–brain barrier (BBB) disruption, and neuroinflammation. Our preliminary studies demonstrate that CRT and CCT synergistically promote CMVEC senescence, with the combined regimen producing greater BBB permeability and CMH burden than either treatment alone. The central hypothesis of this proposal is that CRT and CCT act synergistically to enhance CMVEC senescence, leading to increased vascular fragility and CMH formation, and that clearance of senescent cells with senolytic therapy (Navitoclax, ABT263) will mitigate these outcomes. To test this, Aim 1 will use intravital multiphoton imaging, behavioral assays (neurological scoring, gait analysis), and a novel machine learning–based 3D reconstruction pipeline to quantify therapy-induced microvascular fragility and CMH distribution. Aim 2 will integrate single-cell transcriptomics (scRNA-seq) with 3D cerebrovascular mapping to identify senescence-associated molecular programs and determine whether senolytic therapy restores youthful transcriptomic profiles or engages compensatory protective mechanisms. This research is highly innovative in its integration of cutting-edge imaging, spatial mapping, and single-cell transcriptomics to directly connect molecular programs with structural vascular pathology and functional outcomes. The expected results will establish a mechanistic framework for understanding late-onset cerebrovascular injury in pediatric cancer survivors and evaluate senolytic therapy as a novel strategy to preserve vascular integrity and cognitive function. By defining how cancer therapies accelerate vascular aging and identifying actionable intervention points, this project directly aligns with the American Heart Association’s mission to reduce the burden of stroke, vascular brain injury, and dementia.
Funder: American Heart Association
Amount: $156,200
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2026-01-01
End date: 2027-12-31
Investigators: Dorina Nagy, Dorina Nagy
Institution: Board of Regents of the University of Oklahoma, Health Sciences Center
Funded outputs count: 1
Funder award ID: 26POST1569505
OpenAlex ID: G5688719652