NCS-FO: Developing engineering solutions to investigate microbiome-to-neuron communication

NCS-FO：开发工程解决方案来研究微生物组与神经元的通讯

• 批准号: 1926793
• 负责人: Reza Ghodssi
• 金额: $ 100万
• 依托单位: University of Maryland, College Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1926793&HistoricalAwards=false
• 关键词: NCS; FO; Developing; engineering; solutions

The goal of this project is to create an engineering solution to measure and predict the molecular communication across the gut-microbiome-brain axis. This platform has the potential to facilitate the fundamental understanding of gut microbiome communication with the nervous system. The project will quantify release patterns of key molecules involved in this cross-talk and identify their influence on neural activation and behavior. The gut-microbiome-brain axis, comprising a vast network of nerves innervating the gut and propagating signals to the brain, is a major influencer of behavior and cognition. The neurotransmitter serotonin is a key molecule in this pathway; gut epithelial cells sense luminal conditions and release serotonin to stimulate nearby neurons. The gut microbiome has been shown to mediate this serotonin release, a process that is also linked to the co-occurrence of gastric and neural disorders. The technical underpinnings of this work involve designing and constructing a device that enables researchers to assemble the essential components of the gut-microbiome-neuron tissue interface. The device is fabricated with sensors to obtain information that is currently inaccessible - collecting molecular information at the length and time scales of the cells and tissues under investigation. The data extracted from this platform will enable temporal correlation and prediction of microbial, gut, and neural signaling patterns. This work provides opportunities to bring together researchers and stakeholders from various disciplines including electrical and computer engineering, bioengineering, molecular biology, neuroscience, and data science to develop a system-oriented approach. Further, this project promotes the participation of women, historically underrepresented in engineering, and undergraduates through programs such as Women in Engineering Research Fellowship and First-Year Innovation and Research Experience (FIRE). Multidisciplinary engineering methods are essential to building an in vitro discovery platform capable of directly monitoring chemical transduction patterns along the gut-neuron axis. In TASK 1, electrochemical sensors will be directly fabricated on a porous cell culture substrate, allowing direct access to cellular and molecular mechanisms of an in vitro model gut epithelium. Impedance monitoring of the cell layer will detect physical changes over time (e.g., barrier integrity). Potentiometric monitoring will detect real-time serotonin released from gut cells due to bacterial metabolite stimulation. In TASK 2, the neural effect of gut serotonin signaling will be studied by exposing this cell-released serotonin to an isolated ex vivo crayfish nerve cord with connected and innervated hindgut. Neurobehavioral activation patterns will be recorded during hindgut peristalsis in motor and sensory neurons that bidirectionally connect the central and enteric nervous systems. Machine learning approaches will identify key variables to quantify discrete serotonin release and neuronal activation patterns. In TASK 3, the mucosal layer of the gut epithelium will be colonized with specific gut microbes to assess bacterial influence on barrier integrity, serotonin release patterns, and resulting neuromuscular activation. Classification via machine learning will quantify the wholistic and synergistic effects of different microbial combinations on time-dependent serotonin release profiles and downstream effects. There are multiple novel aspects of this work. First, this is a new platform implementing extensive integrated cell-interfacial sensors for direct access to real-time cell and molecular data. Second, the use of this technology to investigate the interplay between gut and nervous system can give unprecedented insight into the vast and relatively inaccessible gut-brain transduction pathways. Third, machine learning analysis can identify meaningful patterns of serotonergic communication and predict the expected impact of gut bacteria on neural behavior.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.

该项目的目标是创建一种工程解决方案来测量和预测肠道-微生物组-大脑轴上的分子通讯。该平台有潜力促进对肠道微生物组与神经系统通讯的基本理解。该项目将量化参与这种串扰的关键分子的释放模式，并确定它们对神经激活和行为的影响。肠道-微生物组-大脑轴由支配肠道并向大脑传播信号的庞大神经网络组成，是行为和认知的主要影响因素。神经递质血清素是该通路中的关键分子。肠道上皮细胞感知管腔状况并释放血清素以刺激附近的神经元。肠道微生物组已被证明可以介导血清素的释放，这一过程也与胃和神经疾病的同时发生有关。这项工作的技术基础涉及设计和构建一种设备，使研究人员能够组装肠道-微生物组-神经元组织界面的基本组件。该设备配有传感器，可以获取目前无法获取的信息——收集所研究细胞和组织的长度和时间尺度的分子信息。从该平台提取的数据将实现微生物、肠道和神经信号模式的时间关联和预测。这项工作提供了将来自电气和计算机工程、生物工程、分子生物学、神经科学和数据科学等不同学科的研究人员和利益相关者聚集在一起的机会，以开发面向系统的方法。此外，该项目还通过女性工程研究奖学金和第一年创新和研究经验 (FIRE) 等项目，促进历来在工程领域代表性不足的女性和本科生的参与。多学科工程方法对于构建能够直接监测沿肠道神经元轴的化学转导模式的体外发现平台至关重要。在任务 1 中，电化学传感器将直接在多孔细胞培养基质上制造，从而可以直接了解体外模型肠道上皮的细胞和分子机制。细胞层的阻抗监​​测将检测随时间的物理变化（例如屏障完整性）。电位监测将检测由于细菌代谢刺激而从肠道细胞释放的实时血清素。在任务 2 中，将通过将细胞释放的血清素暴露于分离的离体小龙虾神经索（具有相连且受神经支配的后肠）来研究肠道血清素信号传导的神经效应。后肠蠕动期间，双向连接中枢神经系统和肠神经系统的运动和感觉神经元将记录神经行为激活模式。机器学习方法将识别关键变量来量化离散的血清素释放和神经元激活模式。在任务 3 中，肠道上皮的粘膜层将被特定的肠道微生物定植，以评估细菌对屏障完整性、血清素释放模式以及由此产生的神经肌肉激活的影响。通过机器学习进行分类将量化不同微生物组合对时间依赖性血清素释放曲线和下游效应的整体和协同效应。这项工作有多个新颖的方面。首先，这是一个新平台，实现了广泛集成的细胞界面传感器，可直接访问实时细胞和分子数据。其次，利用这项技术来研究肠道和神经系统之间的相互作用，可以对巨大且相对难以接近的肠-脑转导途径提供前所未有的见解。第三，机器学习分析可以识别有意义的血清素通讯模式，并预测肠道细菌对神经行为的预期影响。该奖项反映了 NSF 的法定使命，并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，被认为值得支持。

项目成果

A portable electrochemical sensing platform for serotonin detection based on surface-modified carbon fiber microelectrodes

基于表面修饰碳纤维微电极的便携式血清素检测电化学传感平台

• DOI: 10.1039/d2ay01627c
• 发表时间: 2023-03
• 期刊: Analytical Methods
• 影响因子: 3.1
• 作者: Han, Jinjing;Stine, Justin M.;Chapin, Ashley A.;Ghodssi, Reza
• 通讯作者: Ghodssi, Reza

Ingestible Sensors and Sensing Systems for Minimally Invasive Diagnosis and Monitoring: The Next Frontier in Minimally Invasive Screening

用于微创诊断和监测的可摄入传感器和传感系统：微创筛查的下一个前沿

• DOI: 10.1021/acssensors.9b02263
• 发表时间: 2020-04
• 期刊: ACS Sensors
• 影响因子: 8.9
• 作者: Beardslee, Luke A.;Banis, George E.;Chu, Sangwook;Liu, Sanwei;Chapin, Ashley A.;Stine, Justin M.;Pasricha, Pankaj Jay;Ghodssi, Reza
• 通讯作者: Ghodssi, Reza

A Hybrid Biomonitoring System for Gut-Neuron Communication

用于肠道神经元通讯的混合生物监测系统

• DOI: 10.1109/jmems.2020.3000392
• 发表时间: 2020-01
• 期刊: Journal of Microelectromechanical Systems
• 影响因子: 2.7
• 作者: Chapin, Ashley A.;Han, Jinjing;Ho, Ta;Herberholz, Jens;Ghodssi, Reza
• 通讯作者: Ghodssi, Reza

Freestanding region-responsive bilayer for functional packaging of ingestible devices

用于可摄取设备功能性包装的独立式区域响应双层

• DOI: 10.1038/s41378-023-00536-w
• 发表时间: 2023
• 期刊: Microsystems & Nanoengineering
• 影响因子: 7.9
• 作者: Straker, Michael A. A.;Levy, Joshua A. A.;Stine, Justin M. M.;Borbash, Vivian;Beardslee, Luke A. A.;Ghodssi, Reza
• 通讯作者: Ghodssi, Reza

Electrochemical measurement of serotonin by Au-CNT electrodes fabricated on microporous cell culture membranes

微孔细胞培养膜上制备的 Au-CNT 电极电化学测量血清素

• DOI: 10.1038/s41378-020-00184-4
• 发表时间: 2020-12
• 期刊: Microsystems & Nanoengineering
• 影响因子: 7.9
• 作者: Chapin, Ashley A.;Rajasekaran, Pradeep R.;Quan, David N.;Hu, Liangbing;Herberholz, Jens;Bentley, William E.;Ghodssi, Reza
• 通讯作者: Ghodssi, Reza