CAREER: Closing the Loop on Neuroinflammation

事业：关闭神经炎症循环

• 批准号: 1944053
• 负责人: Levi Wood
• 金额: $ 50万
• 依托单位: Georgia Tech Research Corporation
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1944053&HistoricalAwards=false
• 关键词: CAREER; Closing; Loop; Neuroinflammation

The brain’s immune system is critical for maintaining brain health and cognitive function. Neuroinflammation is responsible for clearing of pathogens and supporting neuron health. However, when neuroinflammation goes out-of-control they can contribute to permanent or progressive cognitive loss in brain injury, Alzheimer’s disease, and many other neurological conditions. Treatment of these diverse diseases would benefit from better understanding of how to regain control of healthy neuroinflammation. Importantly, healthy neuroinflammation is a dynamic process that requires first a pro- followed by an anti-inflammatory response. However, there has been limited investigation to identify the dynamics of healthy neuroinflammation or to determine how to control brain immune cells to restore healthy function. The focus of this CAREER project is microglia, which are the main immune cells of the brain that dynamically respond to pro- and anti-inflammatory stimuli. Their behavior will be explained using quantitative engineering models similar to those used in the design of autopilots. This novel engineering approach will provide new fundamental knowledge on the dynamics of brain immune cells and the relationship between these dynamics and their function to clear pathogens. Moreover, it will enable design of treatments that will promote healthy brain immune function. The Investigator will integrate these research activities with a strong educational outreach program to teach underprivileged elementary school students about the immune system. Planned activities include developing a summer camp on engineering and biological science that includes reinforcement though generation of materials that can be used through-out the school-year and rigorous assessment of student grades and interest in engineering and science. The Investigator's goal is to open the minds of these students to thinking and working as both engineers and scientists and to foster their interest and aspirations to working in STEM fields.The Investigator’s long-term career goal is to create and use engineering methods to elucidate mechanisms driving brain immune function and to actively regulate these mechanisms to reduce immune-based injury and promote brain health. Toward this goal, this CAREER project is to develop a novel paradigm to quantitatively understand the immune cell response to exogenous stimuli and to use this understanding to implement a control system for active regulation of microglia (ARM). The project will create ARM controllers that will regulate multiple markers of diverse microglial states that will be applicable both in vivo and in vitro and will identify quantitative models of microglial cell state dynamics in response to multiple pro- and anti-inflammatory inputs. The research plan is organized under three objectives. The FIRST Objective is to use top-down data driven modeling from control systems engineering to quantify the dynamics of microglial activation in response to biochemical stimuli and use these models to design open-loop control strategies for temporally regulating microglial response in vitro. This will be accomplished through employing flow cytometry to quantify microglial marker dynamics using protein markers known to indicate homeostatic, anti-inflammatory and pro-inflammatory states; identifying a data-driven dynamic system model for each marker; using results obtained to determine the appropriate system input in terms of an optimal control function; and then validating the system by determining whether or not temporal regulation of primary murine microglia response will modify uptake of Amyloid beta, a key pathogen in Alzheimer’s Disease. The SECOND Objective is to determine if quantitative models can be used as part of a real-time feedback strategy to reduce error between desired and actual trajectory of microglial activation. This will be accomplished by establishing a microfluidic cell culture platform to enable real-time feedback control of microglial activation markers; enabling real-time monitoring of microglial activation state via microglial transduction with fluorescent reporters for each of the markers studied in the first objective; and then determining, by placing the microfluidic system and transduced reporter microglia in a live-cell imaging system, if the feed-back control “autopilot” system is capable of regulating a population of microglia to a desired set-point or trajectory. The THIRD Objective is to determine if control systems modeling can be used to model and design open-loop immune trajectories in mice. This will be accomplished by identifying a data-driven model for microglial markers in vivo and combining these dynamic models to predict open-loop input strategies using the same modeling framework as used in the first and second objectives; and then testing if modulation of microglial activity will reduce Amyloid beta pathology in a mouse model of Alzheimer’s disease.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

大脑的免疫系统对于维持大脑健康和认知功能至关重要，神经炎症负责清除病原体并支持神经元健康，但是，当神经炎症失控时，可能会导致脑损伤、阿尔茨海默病等永久性或进行性认知丧失。疾病和许多其他神经系统疾病的治疗将受益于更好地了解如何重新控制健康的神经炎症。重要的是，健康的神经炎症是一个动态的过程，首先需要促进，然后才是。然而，对于确定健康神经炎症的动态或确定如何控制大脑免疫细胞恢复健康功能的研究有限，该职业项目的重点是小胶质细胞，它们是大脑的主要免疫细胞。动态响应促炎和抗炎刺激的大脑将使用类似于自动驾驶仪定量设计中使用的工程模型来解释它们的行为，这种新颖的工程方法将提供有关大脑免疫细胞和抗炎动力学的新基础知识。这些动态及其之间的关系此外，它将有助于设计促进健康大脑免疫功能的治疗方法，研究人员将把这些研究活动与强大的教育推广计划结合起来，向贫困小学生传授免疫系统知识。工程和生物科学夏令营，包括通过生成可在整个学年使用的材料以及严格评估学生的成绩和对工程和科学的兴趣进行强化。研究者的目标是打开这些学生的思想。以工程师和科学家的身份思考和工作培养他们对 STEM 领域工作的兴趣和愿望。研究者的长期职业目标是创建和使用工程方法来阐明驱动大脑免疫功能的机制，并积极调节这些机制，以减少免疫损伤并促进大脑健康。为了实现这一目标，该 CAREER 项目旨在开发一种新颖的范例，以清楚地了解免疫细胞对外源刺激的反应，并利用这种定量理解来实现小胶质细胞主动调节的控制系统 (ARM)。该项目将创建 ARM 控制器。调节多种不同的标记小胶质细胞状态将适用于体内和体外，并将确定小胶质细胞状态动力学响应多种促炎和抗炎输入的定量模型。该研究计划根据三个目标进行组织。 -来自控制系统工程的数据驱动建模，以量化小胶质细胞响应生化刺激的动态，并使用这些模型设计开环控制策略，以在体外暂时调节小胶质细胞反应，这将通过采用流式细胞术来量化来完成。使用已知指示稳态、抗炎和促炎状态的蛋白质标记的小胶质细胞动力学；使用获得的结果确定最佳控制功能的适当系统输入；然后通过确定原代小鼠小胶质细胞反应的时间调节是否会改变淀粉样蛋白（阿尔茨海默病的关键病原体）的摄取来验证该系统。第二个目标是确定定量模型是否可以用作实时反馈的一部分。减少错误的策略这将通过建立微流体细胞培养平台来实现，以实现对小胶质细胞激活标记物的实时反馈控制，并通过每个荧光发生器的小胶质细胞转导来实时监测小胶质细胞的激活状态。第一个目标中研究的标记物；然后通过将微流体系统和转导的报告小胶质细胞放入活细胞成像系统中来确定反馈控制“自动驾驶仪”系统是否能够调节群体第三个目标是确定控制系统模型是否可用于建模和设计小鼠的开环免疫轨迹，这将通过识别小胶质细胞标记的数据驱动模型来实现。体内并结合这些动态模型，使用与第一个和第二个目标中使用的相同的建模框架来预测开环输入策略；然后测试小胶质细胞活性的调节是否会减少阿尔茨海默病小鼠模型中的β淀粉样蛋白病理。奖项反映通过使用基金会的智力价值和更广泛的影响审查标准进行评估，NSF 的法定使命被认为值得支持。

项目成果

Cell type-specific biotin labeling in vivo resolves regional neuronal and astrocyte proteomic differences in mouse brain

体内细胞类型特异性生物素标记解决了小鼠大脑中区域神经元和星形胶质细胞蛋白质组差异

• DOI: 10.1038/s41467-022-30623-x
• 发表时间: 2022-05-25
• 期刊: Nature Communications
• 影响因子: 16.6
• 作者: Rayaprolu, Sruti;Bitarafan, Sara;Santiago, Juliet V.;Betarbet, Ranjita;Sunna, Sydney;Cheng, Lihong;Xiao, Hailian;Nelson, Ruth S.;Kumar, Prateek;Bagchi, Pritha;et al
• 通讯作者: et al

BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia

BIN1 是小胶质细胞促炎和神经退行性相关激活的关键调节因子

• DOI: 10.1186/s13024-022-00535-x
• 发表时间: 2022-05-07
• 期刊: Molecular Neurodegeneration
• 影响因子: 15.1
• 作者: Sudwarts, Ari;Ramesha, Supriya;Gao, Tianwen;Ponnusamy, Moorthi;Wang, Shuai;Hansen, Mitchell;Kozlova, Alena;Bitarafan, Sara;Kumar, Prateek;Beaulieu-Abdelahad, David;Zhang, Xiaolin;Collier, Lisa;Szekeres, Charles;Wood, Levi B.;Duan, Jubao;Thinakaran, Gopal;Rangaraju, Srikant
• 通讯作者: Rangaraju, Srikant

Extracellular signal‐regulated kinase regulates microglial immune responses in Alzheimer’s disease

细胞外信号调节激酶调节阿尔茨海默病中的小胶质细胞免疫反应

• DOI: 10.1002/jnr.24829
• 发表时间: 2021-06
• 期刊: Journal of Neuroscience Research
• 影响因子: 4.2
• 作者: Chen MJ;Ramesha S;Weinstock LD;Gao T;Ping L;Xiao H;Dammer EB;Duong DD;Levey AI;Lah JJ;Seyfried NT;Wood LB;Rangaraju S
• 通讯作者: Rangaraju S