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）和 缺血性中风，这削弱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 可以利用系统发育构成组织修复机制的药理剂来减轻急性 以及次要脑损伤并维持功能恢复。 TBI是美国退伍军人的主要关注点。在TBI存活中，白质损伤与长期有关 功能性缺陷，包括感觉运动，认知和精神障碍。陈实验室将继续 开发增强内源修复过程的修复疗法。在VA功绩评论的支持下，我们 发现大脑先天免疫细胞的功能表型，包括居民小胶质细胞和浸润 血源性巨噬细胞，严格调节白质的微环境，并影响两个白质 伤害和维修。我们最近确定了盐诱导的激酶-1（SIK1），一种进化构成的蛋白 激酶作为一种关键分子开关，该开关控制了TBI之后先天免疫细胞的功能状态。那， 在接下来的四年中，我们将测试遗传缺失或药物抑制SIK1的新假设 通过双重机制改善白质修复和长期TBI结果：1） 通过分解小胶质细胞/巨噬细胞反应和2）增强的早期突触和轴突损伤 慢性阶段白质修复。我们的初步数据表明，SIK1抑制不仅减少了TBI诱导的 感觉运动和认知缺陷，但也与创伤后应激障碍有关的精神症状 （PTSD）。我们认为，这项研究的持续积极成果将加速新颖的发展 通过TBI促进退伍军人成功康复的疗法。 中风是美国退伍军人长期残疾的主要原因。大约11,000名退伍军人 每年住院的新笔触。尽管随着急诊护理的改善，生存有所增加 和新的再通疗，残疾人群继续攀升。对我们的退伍军人的最佳照顾 将需要疗法不仅可以改善脑损伤，而且还会导致脑组织再生 恢复神经功能。冲程后免疫调查对进展有重大影响 缺血性脑损伤和脑恢复，但没有成功利用的临床治疗 免疫系统的恢复能力，同时还会引起感染引起的继发损伤。这 此差距的原因是多因素的，但包括对年​​轻动物的临床前的过分强调， 没有显示出与老年人相同的病理生理机制。在临床上使用 在20个月大的老年小鼠中，相关的中风模型，我们的VA资助的研究帮助我们做出了两个关键发现： 1）至少部分由于小胶质老化，老化大脑从中风恢复的能力大大降低了 小胶质细胞的修复功能受损； 2）老化的小胶质细胞和冲程后脑修复功能 小胶质细胞可以通过激活老年大脑中的类维生素X受体（RXR）来恢复活力。在新的VA资助 研究，我们将测试具有出色安全性的FDA批准的RXR激动剂Bexarotene的能力， 重新激活小胶质细胞的大脑修复增强功能，从而改善长期的中风结果和 老年动物的功能恢复。这是，我们的长期目标是改善中风后退伍军人的生活， 减少其疾病的社会经济伯恩。