Novel neurovascular protective mechanisms of PEDF after subarachnoid hemorrhage

PEDF对蛛网膜下腔出血后神经血管保护的新机制

• 批准号: 10525250
• 负责人: John H Zhang
• 金额: $ 40.3万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525250
• 关键词: Acute; Affinity; Age; Aneurysmal Subarachnoid Hemorrhages; Apoptosis; Apoptotic; Attenuated; Binding; Blood - brain barrier anatomy; Brain; Brain Edema; Brain Injuries; Brain hemorrhage; Cardiac Myocytes; Cell Death; Cell Survival; Cerebrovascular Spasm; Clinical; Data; Deterioration; Disease; Event; Gene Family; Glycoproteins; Goals; Homeostasis; In Vitro; Inflammatory; Injury; Intracranial Aneurysm; Intracranial Hypertension; Intranasal Administration; Ischemia; Link; Lipase; Maintenance; Malignant - descriptor; Mediating; Membrane; Modeling; Molecular; Morbidity - disease rate; Nervous System Physiology; Neurologic; Neurons; Osteoblasts; Outcome; Pathology; Pathway interactions; Patients; Perforation; Rattus; Recombinants; Research; Rodent; Rodent Model; Role; Rupture; Serine Proteinase Inhibitors; Signal Pathway; Stroke; Subarachnoid Hemorrhage; Survivors; Therapeutic; Tissues; Transient Cerebral Ischemia; Vascular Permeabilities; blood-brain barrier disruption; blood-brain barrier permeabilization; cell type; cerebral ischemic injury; clinical translation; granule cell; human fetal retinal pigment epithelial cell; improved; improved outcome; insight; knock-down; macular edema; member; mortality; neurobehavior; neuron apoptosis; neurovascular; new therapeutic target; novel; overexpression; pigment epithelium-derived factor; pigment epithelium-derived factor receptor; protective effect; protective efficacy; protective pathway; protein expression; sex; therapeutic target; transcription factor; treatment strategy

ABSTRACT  Aneurysmal  subarachnoid  hemorrhage  (SAH)  is  a  devastating  type  of  hemorrhagic  stroke  with  50%  mortality and long-­term morbidity in surviving patients.1-­4 Recently, the focus of SAH research has been shifted  to early brain  injury  (EBI)  which  comprises the acute  initial  events after  SAH,  such  as  elevation  of  intracranial  pressure  (ICP),  global  ischemia,  blood  brain  barrier  (BBB)  disruption,  brain  edema  formation,  neuronal  apoptosis,  activation  of  inflammatory  and  cell  death  pathways  that  contribute  to  delayed  neurological  deterioration, leading to mortality and morbidity after SAH.5-­8  Pigment-­epithelium  derived  factor  (PEDF)  is  a  pluripotent  glycoprotein  expressed  in  various  tissues  including  the  brain.9,14  PEDF  reduced  apoptosis  in  various  types  of  cells  including  neurons,14,18  osteoblasts24  and  cardiomyocytes.22  Likewise,  PEDF  reduced  vascular  permeability  and  macular  edema  in  ophthalmologic  pathologies.37,41  There  have  been  relatively  limited  studies  on  the  role  of  PEDF  following  stroke.  PEDF  has  been  shown  to  have  protective  effects  on  neuronal  cell  survival  in  vitro14,18  and  attenuated  cerebral  ischemic  injury  in  rodent  models.19-­21  PEDF  reduced  brain  edema  following  cold-­induced  injury  and  transient  cerebral  ischemia  in  rodent  models.20,21,42  However,  the  role  of  PEDF  following  SAH  has  not  been  explored.  Furthermore,  the  neurovascular  protective  mechanisms  of  PEDF  have  not  been  studied.  This  proposal  will  elucidate  the  neurovascular  protective  mechanisms  of  PEDF  through  anti-­apoptotic  and  BBB  protective pathways in a rodent endovascular perforation SAH model. We will sequentially determine the  role  of  endogenous  PEDF  and  then  evaluate  the  therapeutic  benefits  of  intranasal  administration  of  recombinant PEDF against early brain injury after SAH, specifically neuronal apoptosis and BBB disruption will  be  evaluated.  Additionally,  we  will  elucidate  the  downstream  signaling  pathways  of  PEDF  receptor  (PEDF-­R)  that contribute to anti-­apoptotic and BBB protective mechanisms of PEDF. We propose that PEDF will activate  PEDF-­R/NPD1/Erk1/2-­cRel  pathway  that  reduces  neuronal  apoptosis  with  intranasal  recombinant  PEDF  administration.  Also,  PEDF  activation  of  the  PEDF-­R/Nrf2/HO-­1  pathway  will  contribute  to  BBB  stabilization  after SAH. We will knockdown PEDF receptor and inhibit the pathways to elucidate the mechanism of PEDF-­R  signaling pathway mediated protection.    Overall,  this  proposal  will  provide  novel  insights  into  neurovascular  protective  mechanisms  of  PEDF.  Additionally,  this  proposal  will  establish  the  protective  efficacy  of  intranasal  administration  of  PEDF  as  a  potential therapeutic target against early brain injury after SAH.

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