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Regulation of Viscerosensory Sympathetic Reflexes: The Role of Diet-Derived Lipid Mediators.

内脏感觉交感神经反射的调节：饮食来源的脂质介质的作用。

基本信息

批准号：
10598045
负责人：
Zeljka Minic
金额：
$ 46.07万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598045
关键词：
Acute Afferent Neurons Agonist Animal Model Animals Autonomic Dysreflexia Biochemical Blood Pressure C Fiber Cardiac Cardiovascular system Chronic Clinical Clinical Research Coupling Custom Development Diet Dietary Fatty Acid Disease Electrophysiology (science)Emergency Situation Enteric Nervous System Exposure to Fatty Acids Fecal Impaction Fiber Frequencies Future Gnotobiotic Histopathology Homeostasis Human Hyperreflexia Hypersensitivity Hypertension Hypertensive Crisis Hypertensive Episode Incidence Individual Intestines Knock-out Laboratories Ligands Limb structure Link Linoleic Acids Lipids Modeling Morbidity - disease rate Mus Nerve Neurons Omega-6 Fatty Acids Outcome Paroxysmal Hypertension Pathogenicity Patients Phenotype Physiological Polyunsaturated Fatty Acids Population Preparation Process Production Randomized Rattus Reflex action Regulation Research Rodent Role Sensory Spinal Cord Spinal cord injury Stimulus Systemic blood pressure TRPV1 gene Testing Therapeutic Therapeutic Intervention Vasoconstrictor Agents Vertebral column Virulence Factors Visceral Work antagonist cardiovascular health chronic pain colon distension colorectal distension defined contribution dietary dysbiosis efficacy evaluation fecal transplantation gastrointestinal gut dysbiosis gut microbes gut microbiota hemodynamics improved in vivo insight instrument lipid mediator microbiota mortality neural circuit novel novel therapeutic intervention prevent rational design response small molecule inhibitor targeted treatment treatment strategy

项目摘要

Gastrointestinal and cardiovascular health are intimately linked, yet the mechanism by which diet-derived lipid metabolites and the gut microbial flora impact efferent sympathetic nerve activity is largely unknown. Work from our laboratory and others’ provides increasing evidence that the enteric nervous system directly influences the sympathetic control of systemic blood pressure. The viscerosensory-sympathetic network is a functional neural circuit connecting afferent sensory fibers of the gut and efferent vasoconstrictor neurons at the level of the spinal cord. While this neural circuitry likely influences systemic blood pressure in able-bodied individuals, its role in the development of severe hypertensive crises in patients living with spinal cord injury (SCI) is irrefutable. Autonomic dysreflexia (AD) is often a clinical emergency in SCI individuals and is characterized by paroxysmal hypertension in response to otherwise innocuous visceral stimuli (e.g. fecal impaction). Despite its obvious significance, mechanisms involved in the regulation of viscerosensory-sympathetic reflexes (VSSRs) are poorly understood. Our preliminary studies indicate that C-fiber sensory neurons expressing transient receptor potential cation channel V1 (TRPV1) are involved in the afferent limb of the viscerosensory-sympathetic circuitry. Our proposal seeks to (Aim 1) provide a mechanistic understanding of the role of diet-derived lipid mediators in exaggerating the AD phenotype, (Aim 2) interrogate novel therapeutic strategies for attenuating sympathetic hyperreflexia following SCI, and (Aim 3) define the role of SCI-associated gut dysbiosis in contributing to the production of pathogenic diet-derived lipid mediators. Our central hypotheses identify new pathogenic factors (dietary fatty-acid content and SCI-associated dysbiosis) and a biochemical mechanism (diet-derived TRPV1 lipid ligands) that may be independent targets for therapeutic intervention. Uniquely, our rationally designed therapeutic strategies target the major underlying cause of AD (i.e. visceral C-fiber hypersensitivity) rather than the symptomatic outcome (i.e. acute hypertensive crisis) and thus constitute a major paradigm shift.

胃肠道和心血管健康密切相关，但饮食来源的脂质代谢物和肠道微生物植物群影响传出交感神经活动的机制在很大程度上是未知的。我们实验室和其他实验室的工作提供了越来越多的证据表明肠神经系统直接影响全身血压的交感神经控制。内脏感觉-交感神经网络是连接肠的传入感觉纤维和脊髓水平的传出血管收缩神经元的功能性神经回路。虽然这种神经回路可能会影响身体健全的个体的全身血压，但它在脊髓损伤（SCI）患者严重高血压危象的发展中的作用是无可辩驳的。自主神经反射异常（AD）通常是SCI患者的临床急症，其特征是对无害内脏刺激（如粪便嵌塞）的阵发性高血压反应。尽管内脏感觉-交感神经反射（VSSRs）具有明显的意义，但其调节机制仍知之甚少。我们的初步研究表明，C-纤维感觉神经元表达瞬时受体电位阳离子通道V1（TRPV 1）参与内脏感觉交感神经回路的传入肢。我们的建议旨在（目的1）提供一个机制的理解，饮食来源的脂质介质在夸大AD表型的作用，（目的2）询问新的治疗策略，减轻交感神经反射亢进SCI后，和（目的3）定义SCI相关的肠道生态失调的作用，有助于生产致病的饮食来源的脂质介质。我们的中心假设确定了新的致病因素（膳食脂肪酸含量和SCI相关的生态失调）和生化机制（膳食来源的TRPV 1脂质配体），可能是治疗干预的独立靶点。独特的是，我们合理设计的治疗策略针对AD的主要潜在原因（即内脏C纤维超敏反应），而不是症状性结局（即急性高血压危象），因此构成了一个重大的范式转变。