loading
loading
NIH grant 1I01RD001388-01A2: Nitrated oleic acid-mediated angiogenesis and long-term functional recovery after ischemic stroke
Institute: {'code': 'VA', 'abbreviation': 'VA', 'name': 'Veterans Affairs', 'admin_org_id': '12500964', 'admin_funding_url': ''}. PI: Kejie Yin. Award: $.
Start: 2026-10-01T00:00:00.
Significance to VA: Approximately 15,000 US veterans are hospitalized each year due to stroke, and many
survivors face long-term disabilities. Current therapeutic interventions for stroke are primarily limited to
thrombolytic therapy within a narrow time window. The development of new and effective stroke therapies is
crucially important and urgently needed for both veterans and civilians alike. The proposed study is well
matched to the goals of the ISRM Broad to advance research on the complex needs of military veterans in the
areas of brain, behavioral, and mental health (NOT-RD-01-BMH).
Innovation and Impact: Studies in humans and experimental models of stroke suggest that restoring or
enhancing the cerebral microvascular network through neovascularization in adult brains can improve regional
blood flow and promote recovery after a stroke. Nitro-oleic acid (OA-NO2), a novel endogenous ligand for the
peroxisome proliferator-activated receptor-γ (PPARγ), is found in human plasma, and recent research
highlights its crucial role in regulating angiogenesis. However, the impact of OA-NO2 on cerebral angiogenesis
and long-term functional recovery in the context of ischemic stroke has not been explored. In our preliminary
findings, we are the first to demonstrate that OA-NO2 reduces brain atrophy and improves long-term
neurobehavioral outcomes in a mouse model of ischemic stroke. Furthermore, we are the first to show that
intravenous administration of OA-NO2 significantly promotes the formation and maturation of new cerebral
blood vessels in ischemic mouse brains. These novel findings offer valuable insights into the regulation of brain
vascular remodeling by OA-NO2 and position it as a promising restorative treatment for stroke.
Specific Aims: The major goal of this project is to test our Central Hypothesis that OA-NO2 promotes post-
ischemic cerebral angiogenesis and improves long-term functional recovery after ischemic stroke. Three
specific aims are proposed to test the hypothesis:
• Aim 1: Examine the functional role of OA-NO2 in regulating post-stroke angiogenesis
• Aim 2: Identify the molecular targets of OA-NO2 in regulating post-stroke angiogenesis
• Aim 3: Determine whether OA-NO2-mediated angiogenesis affects long-term stroke outcomes
Methodology: In Aim 1, we will investigate the role of OA-NO2 in post-ischemic cerebral angiogenesis using
C57BL/6J mice treated with OA-NO2 at various doses and times after ischemic stroke. In Aim 2, we will assess
whether OA-NO2 regulates angiogenesis via PPARγ signaling using pharmacological reagents and genetic
approaches (EC-selective PPARγ conditional KO mice). RNA-seq of FACS-sorted brain vascular endothelial
cells will be used to analyze target genes and pathways of OA-NO2 (PPARγ- and non-PPARγ-related) in
treated stroke mice. In Aim 3, we will examine OA-NO2’s role in long-term post-stroke outcomes and its
potential mediation by angiogenesis, using anti-angiogenic compounds and neurobehavioral, MRI, and
morphological approaches.
Path to translation/implementation: To move the research on nitro-oleic acid (OA-NO2) into practice to
improve Veterans healthcare, several key steps are needed. These include optimizing dosage and
administration, conducting expanded animal studies, and performing detailed mechanistic research to
understand OA-NO2's effects. Comprehensive safety evaluations and Phase I-III clinical trials are essential to
establish safety and efficacy.document fetched 2026-10-24 02:46