Role of the PHD2-HIF-VEGF/Epo axis in neurons for neuroplasticity and functional neurological recovery long-term after stroke

• Applicant: Professor Dr. Hugo Marti, since 1/2024
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Anatomy and Physiology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448548502

Although stroke is the second most common cause of death and major cause of long-term disability worldwide, intravenous thrombolysis with tissue-type plasminogen activator and endovascular mechanical thrombectomy are the only clinical therapies currently approved for treatment of acute ischemic stroke. Moreover, apart from physical therapy and cognitive training, there is no therapeutic approach with proven clinical efficacy available that aims to promote brain tissue regeneration and long-term convalescence of neurological functions in stroke patients. Pre-clinical studies have already demonstrated that decline of the oxygen partial pressure during cerebral ischemia initiates adaptive processes in the central nervous system (CNS) that promote both acute neuronal survival and long-term neuroregeneration. The latter comprises angiogenic, neurogenic, and plasticity-related processes. Among others the expression and release of the vascular endothelial growth factor (VEGF) and erythropoietin (Epo) by resident brain cells is increased upon ischemic insult. Both factors not only protect neurons from acute ischemic injury through direct cytoprotective effects, but also control neovascularization of the infarcted tissue, neurogenesis and neuroplasticity. VEGF and Epo are both target genes of the hypoxia-inducible transcription factors (HIFs) whose activity is strictly regulated through the family of prolyl-4-hydroxylase domain (PHD) proteins in an oxygen-dependent manner. Thus, we hypothesize that the PHD-HIF axis is of great importance for the adaption to cerebral ischemia. Accordingly, our preliminary work using murine models of ischemic stroke have demonstrate the following: (1) neuron-specific gene inactivation of the HIF suppressor PHD2 promotes the HIF-dependent genomic response, and reduces brain injury and functional impairment after (sub)acute stroke, (2) neuronal HIF-alpha deficiency worsens tissue injury and functional impairment in the early subacute stage upon stroke, (3) improved brain tissue preservation and sensorimotor function in PHD2 deficient mice is predominantly due to HIF-dependent mechanisms, and (4) systemic treatment with pharmacological PHD inhibitors ameliorates brain tissue damage resulting from acute cerebral ischemia. Based on our preliminary work, the present project aims to clarify whether the PHD/HIF oxygen sensing machinery controls long-term regenerative processes in the CNS post-stroke as well. Along this line, following main issues will be addressed: (i) influence of cell-specific genetic ablation of PHD2 and HIF-alpha in neurons for neuroplasticity and functional recovery after stroke, (ii) importance of HIF-dependent activation of VEGF and Epo for post-stroke neuroplasticity and functional recovery, and (iii) therapeutic efficacy of delayed treatment with PHD inhibitors on structural and functional long-term regeneration after stroke.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Privatdozent Dr. Reiner Kunze, until 12/2023