FGF1 Treatment of Cerebral Vascular Degenerations in blast mTBI

FGF1 治疗急变型 mTBI 中的脑血管变性

• 批准号: 10174852
• 负责人: MIGUEL A GAMA SOSA
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174852
• 关键词: 3-Dimensional; Acoustics; Acute; Affect; Afghanistan; Aneurysm; Angiogenic Factor; Animal Model; Animals; Anxiety; Behavior; Behavioral; Biochemical; Blast Injuries; Blood; Blood Vessels; Blood capillaries; Brain; Cerebrovascular system; Cerebrum; Chronic; Chronic Post Traumatic Stress Disorder; Cognition; Cognitive; Cognitive deficits; Collagen Type IV; Conflict (Psychology); Counseling; Cues; Department of Defense; Development; Disease; Effectiveness; Endothelial Cells; Endothelium; Exhibits; Exposure to; Extracellular Matrix; Extravasation; FGF1 gene; Family member; Fibroblast Growth Factor; Fibronectins; Fright; Functional disorder; Goals; High Prevalence; Histologic; Homeostasis; Human; Immunohistochemistry; Individual; Infusion procedures; Injury; Intranasal Administration; Iraq; Laminin; Learning; Length; Location; Major Depressive Disorder; Medical; Memory; Mental Depression; Mental Health; Methods; Military Personnel; Modeling; Molecular; Molecular Structure; Morphology; Palliative Care; Pathology; Patients; Performance; Phenotype; Post-Traumatic Stress Disorders; Preparation; Process; Property; Publishing; Rattus; Recombinant Fibroblast Growth Factor 1; Recombinants; Research; Role; Services; Signal Transduction; Soldier; Structure; Study models; Symptoms; Testing; Therapeutic; Tissue Harvesting; Traumatic Brain Injury; Treatment Efficacy; Vascular Cognitive Impairment; Vascular remodeling; Veterans; War; Western Blotting; X-Ray Computed Tomography; active method; age related; associated symptom; behavior test; behavioral phenotyping; cerebrovascular; cerebrovascular pathology; conditioned fear; density; efficacy testing; improved; in vivo; microCT; mild traumatic brain injury; morris water maze; neovascularization; neuropsychiatric symptom; neuropsychiatry; novel; novel therapeutics; object recognition; prevent; psychological stressor; reconstruction; response; restoration; stress related disorder; trait; treatment strategy; 3-Dimensional; Acoustics; Acute; Affect; Afghanistan; Aneurysm; Angiogenic Factor; Animal Model; Animals; Anxiety; Behavior; Behavioral; Biochemical; Blast Injuries; Blood; Blood Vessels; Blood capillaries; Brain; Cerebrovascular system; Cerebrum; Chronic; Chronic Post Traumatic Stress Disorder; Cognition; Cognitive; Cognitive deficits; Collagen Type IV; Conflict (Psychology); Counseling; Cues; Department of Defense; Development; Disease; Effectiveness; Endothelial Cells; Endothelium; Exhibits; Exposure to; Extracellular Matrix; Extravasation; FGF1 gene; Family member; Fibroblast Growth Factor; Fibronectins; Fright; Functional disorder; Goals; High Prevalence; Histologic; Homeostasis; Human; Immunohistochemistry; Individual; Infusion procedures; Injury; Intranasal Administration; Iraq; Laminin; Learning; Length; Location; Major Depressive Disorder; Medical; Memory; Mental Depression; Mental Health; Methods; Military Personnel; Modeling; Molecular; Molecular Structure; Morphology; Palliative Care; Pathology; Patients; Performance; Phenotype; Post-Traumatic Stress Disorders; Preparation; Process; Property; Publishing; Rattus; Recombinant Fibroblast Growth Factor 1; Recombinants; Research; Role; Services; Signal Transduction; Soldier; Structure; Study models; Symptoms; Testing; Therapeutic; Tissue Harvesting; Traumatic Brain Injury; Treatment Efficacy; Vascular Cognitive Impairment; Vascular remodeling; Veterans; War; Western Blotting; X-Ray Computed Tomography; active method; age related; associated symptom; behavior test; behavioral phenotyping; cerebrovascular; cerebrovascular pathology; conditioned fear; density; efficacy testing; improved; in vivo; microCT; mild traumatic brain injury; morris water maze; neovascularization; neuropsychiatric symptom; neuropsychiatry; novel; novel therapeutics; object recognition; prevent; psychological stressor; reconstruction; response; restoration; stress related disorder; trait; treatment strategy

Summary      Blast-­related traumatic brain injury (TBI) is associated with the development of neuropsychiatric injuries  (including post-­traumatic stress disorder [PTSD] and major depression) among soldiers in the war theaters of  Iraq and Afghanistan. Treatment for blast-­related TBI is currently limited to counseling and palliative care. We  have explored the effects of 74.5-­kPa blast exposures that mimic mild TBI (mTBI) in a rat model. Blast-­ exposed rats exhibit a variety of PTSD-­like behavioral traits, including increased anxiety, enhanced acoustic  startle, altered responses to a predator scent, and altered cued fear responses. Further experimental evidence  indicates that the cerebral vasculature is a main target for blast waves, as acute and chronic vascular  degenerative processes develop after blast-­exposures. Previous research has shown that fibroblast growth  factor 1 (FGF1) is a strong angiogenic factor that can induce neovascularization, capillary branching, and  vascular remodeling. We have published evidence indicating that FGF signaling is essential for endothelial cell  homeostasis and survival.   The overall goal of the proposed research is to test whether intranasal administration of FGF1 can  reverse the established cerebrovascular and cognitive degenerative processes present in our rat model of  blast-­induced mTBI. We propose to administer recombinant FGF1 into blast-­exposed rats (3 × 74.5 kPa) once  they have developed the chronic PTSD phenotype (6 months post-­blast exposure) to test whether this  treatment improves the cognitive deficits and vascular alterations associated with these diseases. We will test  for memory (Morris Water Maze), contextual and cued fear conditioning, and novel object recognition. Using X-­ ray CT, immunohistochemical and stereological methods we will analyze alterations in large vessels and in the  microvasculature, including the presence of abnormal vasculature and changes in vascular density, length, and  volume. Biochemical analyses will identify any molecular structural changes in the microvasculature induced  by FGF1 treatment.   Collectively, the proposed studies will explore the potential therapeutic benefits of FGF1 for the treatment  of  blast-­induced  PTSD.  These  studies  may  uncover  new  therapeutic  options  for  the  treatment  of  active  duty  military personnel and veterans affected by this devastating condition.

概括   与爆炸有关的创伤性脑损伤（TBI）与神经精神损伤的发展有关 （包括创伤后应激障碍[PTSD]和主要定义） 伊拉克和阿富汗。目前，与BLAST相关的TBI的治疗仅限于计数和姑息治疗。我们 已经探索了在大鼠模型中模仿轻度TBI（MTBI）的74.5 kPa爆炸暴露的影响。爆炸 暴露的大鼠暴露了各种PTSD样行为特征，包括焦虑增加，声音增强 惊吓，改变了对捕食者的反应，并改变了提示的恐惧反应。进一步的实验证据 表明大脑血管是急性和慢性血管的主要目标 爆炸后的退化过程开发。先前的研究表明成纤维细胞生长 因子1（FGF1）是一个强大的血管生成因子，可以诱导新血管形成，毛细管分支和 血管重塑。我们发表了证据，表明FGF信号对于内皮细胞至关重要 稳态和生存。 拟议研究的总体目标是测试鼻内施用FGF1是否可以 扭转我们的大鼠模型中既定的脑血管和认知退化过程 爆炸引起的mtbi。我们建议将重组FGF1施用到暴露于爆炸的大鼠（3 x 74.5 kPa）中 他们已经开发了慢性PTSD表型（Blast暴露后6个月），以测试是否 治疗可改善与这些疾病相关的认知缺陷和血管改变。我们将测试 用于记忆（莫里斯水迷宫），上下文和提示的恐惧调节以及新颖的对象识别。使用X- 射线CT，免疫组织化学和立体方法，我们将分析大容器和 微脉管系统，包括存在异常脉管系统以及血管张力，长度和 体积。生化分析将确定微脉管系统中的任何分子结构变化 通过FGF1治疗。 总的来说，拟议的研究将探索FGF1的潜在治疗益处 爆炸引起的PTSD。这些研究可能会发现用于治疗现役的新治疗选择 受到这种毁灭性状况影响的军事人员和退伍军人。