The Structural and Molecular Basis of Blast-Induced Vascular Injury

爆炸引起的血管损伤的结构和分子基础

• 批准号: 10158420
• 负责人: Gregory A. Elder
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158420
• 关键词: Acute; Affect; Afghanistan; Alzheimer' s disease model; Area; Astrocytes; Basement membrane; Behavior; Behavioral; Biochemical Markers; Biotin; Blast Injuries; Blood - brain barrier anatomy; Blood Vessels; Brain Injuries; Cerebrovascular system; Cerebrum; Chronic; Chronic Phase; Cognitive; Complement; Computer software; Conflict (Psychology); Data; Dextrans; Electron Microscopy; Evolution; Glial Fibrillary Acidic Protein; Histologic; Hour; Immunohistochemistry; Injury; Intermediate Filament Proteins; Iraq; Label; Length; Mass Spectrum Analysis; Mental Health; Modeling; Molecular; Morbidity - disease rate; Nerve; Neurofilament-H; Neurons; Pathology; Pericytes; Post-Traumatic Stress Disorders; Preparation; Process; Property; Proteins; Proteomics; Rattus; Research; Research Personnel; Role; Scanning; Smooth Muscle; Structure; Surface; Techniques; Testing; Time; Traumatic Brain Injury; Veterans; Western Blotting; aquaporin 4; attenuation; behavior test; behavioral phenotyping; blast exposure; density; improved; metabotropic glutamate receptor 2; microCT; mild traumatic brain injury; military service; mortality; mouse model; neurofilament; neurovascular; neurovascular unit; novel; novel therapeutic intervention; receptor; stress related disorder; trait; treatment strategy; vascular injury

Traumatic  brain  injury  (TBI)  has  been  a  major  cause  of  mortality  and  morbidity  in  the  recent  conflicts  in  Iraq  and  Afghanistan.  Much  concern  exists  over  the  role  of  TBI  in  the  chronic  cognitive and behavioral effects that can develop during or after military service. Most injuries in  the  recent  conflicts  have  been  mild  TBIs  (mTBIs)  due  to  blast  exposure.  Vascular  damage  is  well  established  as  a  significant  component  of  blast  injury.  Indeed  under  the  conditions  of  exposure in the model under study at the histological level the cerebral vasculature seems to be  selectively  vulnerable.  Using  micro  computed  tomography  (CT)  scanning  we  found  that  blast  induces  widespread  attenuation  of  the  brain  vasculature.  In  proteomic  studies  on  isolated  microvascular  preparations  obtained  two  months  following  injury  one  of  the  most  highly  altered  proteins  identified  by  mass  spec  (MS)  was  found  to  be  glial  fibrillary  acidic  protein  (GFAP),  which  was  decreased  by  blast-­exposure.  This  finding  was  confirmed  by  Western  blotting  on  isolated  microvascular  preps.  The  loss  of  GFAP  seemed  to  suggest  that  following  blast  injury  astrocytic  endfeet  were  becoming  detached  from  cerebral  vessels  and  immunostaining  of  isolated  microvascular  preps  supported  this  speculation.  Interestingly  of  the  first  9  proteins  identified  by  MS  several  others  were  neuronal  intermediate  filament  proteins  including  the  neurofilament heavy chain (NF-­H) and α-­ internexin, which like GFAP, were decreased following  blast  injury.  Loss  of  these  proteins  suggests  that  nerve  terminals  become  detached  from  cerebral  vessels  as  well.  Disrupted  gliovascular and  neurovascular  connections  could  affect  a  number  of  cerebral  functions.  The  proposed  studies  will  determine  the  chronic  structural  and  functional  consequences  of  blast  injury  on  the  vasculature  in  a  rat  model  of  low-­level  blast  exposure.  The  studies  will  utilize  quantitative  immunohistochemistry,  stereology,  electron  microscopy,  Western blotting  of  isolated  microvascular preps,  micro  CT  scanning and  behavior.  We  will  test  the  hypothesis  that  blast  injury  causes  widespread  loss  of  gliovascular  and  neurovascular connections and determine the functional consequences. We will also determine  whether  a  treatment  that  improves  the  post-­traumatic  stress  disorder  (PTSD)-­related behavioral  traits  that  develop  in  this  model  stimulates  gliovascular  and  neurovascular  connections  as  well  improves the vascular pathology observed on micro CT scanning. Three-­time points post-­ blast exposure  will  be  examined  (48 hours,  6  weeks  and  8  months)  to  capture the  evolution  of  the injury from acute into subacute and chronic phases.

近年来，外伤性脑损伤（TBI）已成为导致死亡和发病的主要原因之一