BLRD Research Career Scientist Award Application

Chen实验室的研究重点是减轻创伤性脑损伤（TBI）的神经后遗症， 缺血性中风，这降低了退伍军人的生活质量。我们的目标是帮助识别和/或开发 可以利用遗传学上保守的组织修复机制来缓解急性炎症的药物 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TBI幸存者中，白色物质损伤与长期脑损伤相关。 功能缺陷，包括感觉运动、认知和精神障碍。Chen实验室将继续 开发增强内源性修复过程的恢复疗法。在VA Merit Review的支持下， 发现大脑先天免疫细胞的功能表型，包括常驻小胶质细胞和浸润性 血液传播的巨噬细胞，关键地调节白色物质中的微环境，并影响白色物质 损伤和修复。我们最近发现了盐诱导激酶-1（SIK 1），一种进化上保守的蛋白质 激酶，作为控制TBI后先天免疫脑细胞功能状态的关键分子开关。因此，在本发明中， 在接下来的四年里，我们将测试新的假设，即基因缺失或药物抑制SIK 1 通过双重机制改善白色物质恢复和长期TBI结果： 通过炎症消退的小胶质细胞/巨噬细胞反应引起的早期突触和轴突损伤，以及2）增强 慢性期白色物质修复。我们的初步数据表明，SIK 1抑制不仅减少了TBI诱导的 感觉运动和认知缺陷，以及与创伤后应激障碍相关的精神症状 （PTSD）。我们相信，这项研究的持续积极成果将加速新技术的发展。 促进TBI退伍军人成功康复的治疗。 中风是美国老年退伍军人长期残疾的主要原因。大约有11，000名退伍军人 每年因新发中风住院尽管随着急救护理的改善， 和新的血管再通治疗，残疾人口继续攀升。最佳护理我们的退伍军人 将需要治疗，不仅改善脑损伤，而且还导致脑组织再生， 恢复神经功能。中风后免疫反应对中风的进展有实质性的影响。 缺血性脑损伤和脑恢复，但没有临床治疗，成功地利用 免疫系统的恢复能力，同时也缓和炎症引起的继发性损伤。的 造成这一差距的原因是多方面的，但包括临床前对年轻成年动物的过度使用， 没有显示出与老年人相同的脑缺血病理生理机制。使用临床 在20个月大的老龄小鼠中建立相关中风模型，我们的VA资助的研究帮助我们做出了两个关键发现： 1)老年大脑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 和受损的小胶质细胞的修复功能; 2）老年小胶质细胞和中风后脑修复功能， 小胶质细胞可以通过激活衰老大脑中的类维生素A X受体（RXR）来恢复活力。在新的VA资助的 研究，我们将测试贝沙罗汀，一种FDA批准的RXR激动剂，具有良好的安全性， 重新激活小胶质细胞的大脑修复增强功能，从而改善长期中风结局， 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， 减轻残疾人的社会经济负担。

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.