Developing a comprehensive model for peripheral nerve stimulation of gastrointestinal function

开发胃肠功能周围神经刺激的综合模型

基本信息

批准号：
10560025
负责人：
Xiling Shen
金额：
$ 47.96万
依托单位：
TERASAKI INSTITUTE FOR BIOMEDICAL INNOVATION
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10560025
关键词：
Afferent Neurons Alternative Therapies Animal Model Animals Biomedical Computing Calcium Colon Computer Models Constipation Data Development Disease Dyspepsia Engineering Enteral Enteric Nervous System FOS gene Fecal Incontinence Feedback Fiber Functional Gastrointestinal Disorders Future Gastrointestinal Motility Gastrointestinal tract structure Goals Image Incontinence Interneurons Interstitial Cell of Cajal Intervention Irritable Bowel Syndrome Lead Location Magnetism Measures Mediating Modeling Motor Neurons Mus Muscle Muscle Fibers Nerve Nervous system structure Neurons Organ Outcome Output Pathway interactions Pattern Peripheral Peripheral Nerve Stimulation Peripheral Nerves Persons Pharmacologic Substance Pharmacology Rattus Regulation Resort Rodent Sacral nerve Smooth Muscle System Testing Therapeutic Time Transgenic Animals United States National Institutes of Health Universities Vagus nerve structure Validation Visceral awake base bioelectronics cell motility experimental study gastrointestinal function gastrointestinal system improved in silico in vivo inhibitor insight interest mathematical model models and simulation motility disorder nerve supply nodal myocyte novel particle scaffold sensor sex therapeutic development tool

项目摘要

SUMMARY One in five people suffer from some form of functional gastrointestinal and motility disorders (FGIMD), a group of diseases caused by malfunction of the enteric (gut) nervous system (ENS), including irritable bowel syndrome, fecal incontinence, constipation, dyspepsia, and others. Pharmaceutical intervention is largely unsuccessful at managing these conditions. Recently, electrical sacral nerve stimulation (SNS) has emerged as an alternative therapy for FGIMD. However, how the sacral nerves innervate and modulate the ENS is unknown, so clinicians have to resort to one set of empirical stimulation parameters in hopes of relieving different (sometimes opposite) conditions, with very inconsistent outcomes. The objective of this project is to understanding how the sacral nerves innervate and modulate the enteric nervous system. We pose three hypothetical mechanisms through which SNS modulates gut motility: SNS modulates [a] enteric neurons, [b] smooth muscle, and / or [c] intrinsic pacemaker cells. The challenge is that there is no specific tool, such as pharmacological blockers, transgenic animal models, etc., that can distinguish these three hypothetical mechanisms in vivo. To overcome this challenge, we will build the first computational model that integrates the sacral nerves, the ENS, and GI motility. For each hypothetic mechanism, the in silico framework will predict distinct neuron and muscle firing patterns, which can then be experimentally validated in vivo by c-Fos+ immunomapping and intravital colon imaging. The in silico framework will also predict motility patterns during SNS, which will be validated by implantable motility sensors in awake animals. Once the fundamental mechanism of the SNS-ENS interface is understood, we will use the improved in silico model to optimize SNS parameters that maximally increase or decrease colonic motility, followed by in vivo validation. In summary, we will combine computational modeling and in vivo experiments to determine how the sacral nerves innervate and modulate the ENS and GI motility. Our model will provide fundamental understanding of how peripheral nerves interface with an organ, which is generalizable to other types of peripheral nerves such as the vagus nerve. The model will also enable us to test the hypothesis that specific stimulation patterns can be delivered to treat different conditions in the lower GI system, rather than using the current one-size-fits-all, hit-or-miss approach.

概括五分之一的人患有某种形式的功能性胃肠道和动力障碍 (FGIMD) 由肠（肠）神经系统（ENS）功能障碍引起的疾病，包括肠易激综合症，大便失禁、便秘、消化不良等。药物干预在很大程度上并不成功管理这些条件。最近，骶神经电刺激（SNS）已成为一种替代方案 FGIMD 的治疗。然而，骶神经如何支配和调节 ENS 尚不清楚，因此临床医生必须求助于一组经验刺激参数，以期缓解不同的（有时是相反的）条件，结果非常不一致。该项目的目的是了解骶神经如何支配和调节肠神经系统。我们提出了 SNS 调节肠道运动的三种假设机制：调节 [a] 肠神经元、[b] 平滑肌和/或 [c] 内在起搏细胞。挑战在于没有特定的工具，如药理阻断剂、转基因动物模型等，可以区分这三种假设的体内机制。为了克服这一挑战，我们将建立第一个集成骶神经的计算模型 ENS 和 GI 活力。对于每种假设机制，计算机框架将预测不同的神经元和肌肉放电模式，然后可以通过 c-Fos+ 免疫图谱在体内进行实验验证，活体结肠成像。计算机框架还将预测 SNS 期间的运动模式，这将是通过清醒动物体内的植入式运动传感器进行验证。一旦SNS-ENS的基本机制接口理解后，我们将使用改进的计算机模型来优化 SNS 参数，最大程度地增加或减少结肠运动，然后进行体内验证。总之，我们将结合计算模型和体内实验来确定骶骨如何神经支配并调节 ENS 和 GI 运动。我们的模型将提供对以下内容的基本理解周围神经如何与器官连接，这可以推广到其他类型的周围神经，例如作为迷走神经。该模型还将使我们能够检验特定刺激模式可以用于治疗下胃肠道系统的不同病症，而不是使用当前的一刀切，碰运气的方法。