BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10696455
• 负责人: Jun Chen
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2030-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696455
• 关键词: Acceleration; Acute; Affect; Aging; Agonist; Alteplase; Animals; Anti-Inflammatory Agents; Area; Attention; Award; Bexarotene; Biological; Blood Vessels; Brain; Brain Injuries; Brain Ischemia; Caring; Cells; Cerebrovascular Circulation; Chronic; Clinical Treatment; Cognitive; Cognitive deficits; Collaborations; Data; Development; Disabled Persons; Economic Burden; Elderly; Emergency Care; FDA approved; Female; Funding; Future; Generations; Genetic; Goals; Grant; Grant Review; Growth; HSPB1 gene; Health; Health system; Healthcare; Hospitalization; Immune; Immune response; Immune system; Immunity; Impaired cognition; Impairment; Infiltration; Inflammation; Injury; Institution; Interleukin-4; Ischemic Brain Injury; Ischemic Stroke; Journals; Level of Evidence; Macrophage; Manuscripts; Medical center; Metabolism; Microglia; Molecular; Moods; Mus; National Institute of Neurological Disorders and Stroke; Natural regeneration; Nervous System Physiology; Neurologic; Omega-3 Fatty Acids; Outcome; Outcomes Research; Paper; Peer Review; Personal Satisfaction; Phenotype; Phylogenetic Analysis; Population; Post-Traumatic Stress Disorders; Process; Protein Kinase; Publications; Quality of life; RXR; Recovery; Recovery of Function; Regulatory T-Lymphocyte; Rehabilitation therapy; Rejuvenation; Reporting; Research; Research Personnel; Role; Safety; Scientist; Stroke; Survivors; Synapses; System; TBI treatment; Testing; Therapeutic; Thinking; Tissues; Trauma; Traumatic Brain Injury; Traumatic Brain Injury recovery; United States National Institutes of Health; Universities; Veterans; Work; aged; aging brain; axon injury; blood-brain barrier disruption; brain cell; brain repair; brain tissue; career; clinical investigation; clinically relevant; cognitive function; cytokine; disability; effective therapy; glial activation; improved; indexing; injury and repair; injury recovery; long term recovery; male; mature animal; military veteran; neurological recovery; novel; novel therapeutics; pharmacologic; post stroke; pre-clinical; programs; psychiatric symptom; repair function; repaired; response; restoration; salt-inducible kinase; socioeconomics; stroke model; stroke outcome; stroke victims; tissue repair; white matter; white matter injury; young adult

Research in the Chen lab focuses on alleviating the neurological sequelae of traumatic brain injury (TBI) and ischemic stroke, which diminish our veterans’ quality of life. Our goals are to help identify and/or develop pharmacologic agents that can leverage phylogenetically conserved tissue-repair mechanisms to alleviate acute and secondary brain damage and sustain functional recovery. TBI is a major concern for US military veterans. In TBI survivors, white matter injury is associated with long-term functional deficits, including sensorimotor, cognitive, and psychiatric impairments. The Chen lab will continue to develop restorative therapies that augment endogenous repair processes. Supported by VA Merit Review, we found that the functional phenotypes of brain innate immune cells, including resident microglia and infiltrating blood-borne macrophages, critically regulate the microenvironment in white matter and impact both white matter injury and repair. We have recently identified salt-inducible kinase-1 (SIK1), an evolutionarily conserved protein kinase, as a key molecular switch that governs the functional states of innate immune brain cells after TBI. Thus, in the next four years, we will test the new hypotheses that genetic deletion or pharmacological inhibition of SIK1 improves white matter restoration and long-term TBI outcomes through dual mechanisms: 1) protecting against early synaptic and axonal injury by inflammation-resolving microglia/macrophage responses, and 2) enhancing chronic-stage white matter repair. Our preliminary data suggest that SIK1 inhibition not only reduces TBI-induced sensorimotor and cognitive deficits, but also the psychiatric symptoms relevant to post-traumatic stress disorder (PTSD). We believe that continued positive outcomes of this research will accelerate the development of novel therapies to promote successful rehabilitation of veterans with TBI. Stroke is a leading cause of long-term disability in elderly US veterans. Approximately 11,000 veterans are hospitalized annually with new strokes. Although survival has increased with improvements in emergency care and new recanalization therapy, the population with disabilities continues to climb. Optimal care of our veterans will require therapies that not only ameliorate brain injury—but also lead to regeneration of brain tissue and restoration of neurological function. Post-stroke immune responses have a substantial impact on the progression of ischemic brain injury and brain recovery, but there are no clinical treatments that successfully harness the restorative power of the immune system while also tempering inflammation-induced secondary injuries. The reasons for this gap are multifactorial, but include a preclinical overemphasis on young adult animals, which do not display the same pathophysiological mechanisms underlying brain ischemia as the aged. Using a clinically relevant stroke model in 20-month old aging mice, our VA-funded research helped us make two key discoveries: 1) the remarkably reduced ability of aged brains to recover from stroke is, at least in part, due to microglial aging and the impaired reparative functions of microglia; 2) aged microglia and post-stroke brain-repair functions of microglia can be rejuvenated by activating the retinoid X receptor (RXR) in the aged brain. In the new VA-funded research, we will test the ability of bexarotene, an FDA-approved RXR agonist with excellent safety profiles, to reactivate the brain repair-enhancing functions of microglia, thereby improving long-term stroke outcomes and functional recovery in aged animals. Thus, our long-term goals are to improve veterans’ lives after stroke and reduce the socioeconomic burden of their disabilities.

陈实验室的研究重点是减轻创伤性脑损伤(TBI)的神经后遗症和 缺血性中风，这降低了我们退伍军人的生活质量。我们的目标是帮助识别和/或开发 可以利用系统发育保守的组织修复机制来缓解急性呼吸窘迫综合征的药物 和继发性脑损伤，并维持功能恢复。 TBI是美国退伍军人的主要担忧。在脑外伤幸存者中，脑白质损伤与长期的 功能缺陷，包括感觉运动、认知和精神障碍。陈实验室将继续 开发增强内源性修复过程的恢复性疗法。在退伍军人事务部功绩审查的支持下，我们 发现脑内天然免疫细胞的功能表型包括驻留的小胶质细胞和浸润性 血液中的巨噬细胞，对白质中的微环境起着关键的调节作用，并影响着两个白质 受伤和修复。我们最近发现了盐诱导蛋白-1(SIK1)，这是一种进化上保守的蛋白 作为调节脑外伤后先天免疫脑细胞功能状态的关键分子开关。因此， 在接下来的四年里，我们将测试新的假设，即SIK1的基因缺失或药物抑制 通过双重机制改善脑白质恢复和长期脑损伤预后：1)保护 炎症溶解小胶质细胞/巨噬细胞反应引起的早期突触和轴突损伤，以及2)增强 慢性期白质修复。我们的初步数据表明，抑制SIK1不仅可以减少脑损伤诱导的 感觉运动和认知障碍，以及与创伤后应激障碍相关的精神症状 (创伤后应激障碍)。我们相信，这项研究的持续积极成果将加速小说的发展 促进脑外伤退伍军人成功康复的治疗。 中风是导致美国退伍军人长期残疾的主要原因。大约11,000名退伍军人 每年因新的中风而住院。尽管随着急救护理的改善，存活率有所提高 和新的血管再通疗法，残疾人口继续攀升。为退伍军人提供最佳护理 将需要的治疗不仅要改善脑损伤-而且还能导致脑组织再生和 神经功能的恢复。卒中后的免疫反应对病情进展有重大影响 缺血性脑损伤和脑康复，但还没有临床治疗方法成功地利用 恢复免疫系统的能力，同时也缓和炎症引起的继发性损伤。这个 造成这一差距的原因是多方面的，但包括临床前过度强调年轻成年动物，这确实是 不表现出与老年人相同的脑缺血的病理生理机制。在临床上使用 为了在20个月大的老龄小鼠中建立相关的中风模型，我们由退伍军人管理局资助的研究帮助我们取得了两项关键发现： 1)老年人从中风中恢复的能力显著降低，至少部分是由于小胶质细胞的老化 2)衰老的小胶质细胞与卒中后的脑修复功能 小胶质细胞可以通过激活老年大脑中的维甲酸X受体(RXR)来恢复活力。在退伍军人事务部资助的新项目中 在这项研究中，我们将测试贝沙罗汀，一种FDA批准的RXR激动剂，具有极好的安全性， 重新激活小胶质细胞促进大脑修复的功能，从而改善中风的长期结果和 老年动物的功能恢复。因此，我们的长期目标是改善退伍军人中风后的生活和 减轻残疾人的社会经济负担。