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Direct assessment of distal small fiber neuropathy in models of neurotoxicity

神经毒性模型中远端小纤维神经病变的直接评估

基本信息

批准号：
7786240
负责人：
Elena Zotova
金额：
$ 20.54万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7786240
关键词：
Acquired Immunodeficiency Syndrome Affect Analgesics Anatomy Animal Model Antibodies Axon Behavior Behavioral Biological Markers Brain C Fiber Caliber Capsaicin Cells Clinical Clinical assessments Complement Data Degenerative polyarthritis Development Diabetes Mellitus Disease Distal Dose-Limiting Evaluation Experimental Models Fatigue Fiber Frequencies Functional disorder Genetic Human Investigation Ions Ixabepilone Knowledge Laboratories Measurement Measures Methods Microtubule stabilizing agent Mitochondria Modeling Nature Nerve Nerve Fibers Nerve Growth Factors Neural Conduction Neuraxis Neuroglia Neurons Neuropathy Neurotoxins Pain Pattern Peripheral Nervous System Peripheral Nervous System Diseases Pharmacologic Substance Phase Play Procedures Process Rattus Reaction Receptor Protein-Tyrosine Kinases Recovery Research Design Role Secondary to Sensitivity and Specificity Sensory Signal Transduction Site Skin Solid Neoplasm Subcellular Anatomy Substance P Surface Tail Techniques Time Toxic effect Toxin Withdrawal axonopathy base cancer therapy chemotherapy density design digital human disease improved inhibitor/antagonist neurogenesis neurotoxic neurotoxicity neurotrophic factor novel pre-clinical public health relevance relating to nervous system response spinal pathway standard measure tool vocalization

项目摘要

DESCRIPTION (provided by applicant): This proposal is designed to improve the sensitivity, specificity and validity of animal models of small fiber toxic neuropathy (SFTN) by developing a novel electrophysiological method for the direct, non-invasive assessment of conduction in small diameter axons (A4 and C fibers). Damage to these fibers is a key component of pain, the loss of thermal sensitivity and autonomic deficits induced by neurotoxic exposures (e.g., chemotherapy, industrial or environmental toxicity). Available models for SFTN are limited and the pathophysiology of these abnormalities is poorly understood. The outlined studies will apply a technique of multiple unit recordings, originally developed to measure intracortical conduction in the central nervous system, to the assessment of slow (less than 2.5 m/sec) and asynchronous activity in peripheral nervous system. They also employ techniques of high frequency stimulation to evaluate the hypothesis that small diameter axons are especially vulnerable to deficits in local energy utilization and reserves. The outlined methods will be used to explore SFTN in two distinct animal models of toxic neuropathy: ixabepilone (IXA), a new microtubule-stabilizing agent, and capsaicin (CAP), a local analgesic. IXA impairs both large and small diameter axons and neuropathy is a serious dose-limiting factor of this new anti-cancer treatment. The outlined studies will focus on differences in the onset, pattern, magnitude and degree of recovery of deficits across fiber types, with an emphasis on previously undocumented changes in SFTN. To our knowledge these will be the first comprehensive investigations of animal models of IXA-induced neuropathy. CAP targets substance P-containing axons and evokes an exclusive SFTN. These studies will focus on the development of a non-invasive functional biomarker of activity in the extreme terminal regions on intraepidermal sensory axons. The non-invasive measurement of conduction in small diameter myelinated and unmyelinated axons would provide an alternative and/or complementary measure to the assessment of intraepidermal nerve fiber density (IENFD). In each model, SFTN will be evaluated using surface non-invasive procedures in the most distal segments of both the caudal and digital nerves. Electrophysiological data will be compared to the histopathological changes in a full spectra of nerve fibers (A12, A4 and C fibers) along a distal-to- proximal gradient. If successful, the outlined studies will expand the utility of nerve conduction measures and will provide a new objective and sensitive biomarker for SFTN. The outlined studies will thus greatly improve the utility of existing animal models of a variety of toxic neuropathies, including those associated with chemotherapy, and will provide a new tool for the clinical and preclinical assessment of nerve damage associated with many human diseases including diabetes, AIDS, and genetic neuropathies. PUBLIC HEALTH RELEVANCE: Project Narrative These studies will provide a novel biomarker for toxin-induced or disease-related deficits in the function of small diameter myelinated and unmyelinated axons (A4 and C fibers). Although these axons play a key role in processing pain, thermal sensitivity and autonomic function and are the predominant fiber type in most nerves, they are poorly measured by existing techniques and are therefore understudied. If successful, the outlined studies will greatly improve the utility of existing animal models of a variety of toxic neuropathies, including those associated with chemotherapy, and will provide a new tool for the clinical and preclinical assessment of nerve damage associated with many human diseases including diabetes, AIDS, and genetic neuropathies.

描述（由申请人提供）：本提案旨在通过开发一种用于直接、无创评估小直径轴突（A4和C纤维）传导的新型电生理学方法，提高小纤维毒性神经病（SFTN）动物模型的灵敏度、特异性和有效性。对这些纤维的损伤是疼痛、热敏感性丧失和神经毒性暴露诱导的自主神经缺陷的关键组成部分（例如，化学疗法、工业或环境毒性）。SFTN的可用模型是有限的，这些异常的病理生理学知之甚少。概述的研究将应用最初开发用于测量中枢神经系统皮质内传导的多单位记录技术，以评估外周神经系统的缓慢（小于2.5 m/sec）和异步活动。他们还采用高频刺激技术来评估小直径轴突特别容易受到局部能量利用和储备不足的影响的假设。概述的方法将被用来探讨SFTN在两个不同的动物模型中的毒性神经病变：伊沙匹隆（IXA），一种新的微管稳定剂，和辣椒素（CAP），局部镇痛剂。IXA损害大直径和小直径轴突，并且神经病变是这种新抗癌治疗的严重剂量限制因素。概述的研究将侧重于不同纤维类型的缺陷的发病，模式，幅度和恢复程度的差异，重点是以前未记录的SFTN变化。据我们所知，这将是第一次全面调查的动物模型的IXA诱导的神经病变。CAP靶向含有P物质的轴突并引起专属SFTN。这些研究将集中于开发一种非侵入性的功能性生物标志物，用于检测表皮内感觉轴突末端区域的活性。小直径有髓和无髓轴突的传导的非侵入性测量将提供表皮内神经纤维密度（IENFD）评估的替代和/或补充测量。在每个模型中，将使用表面非侵入性手术在尾神经和指神经的最远段评价SFTN。将电生理学数据与神经纤维（A12、A4和C纤维）沿着从远端到近端梯度的全光谱中的组织病理学变化进行比较。如果成功，概述的研究将扩大神经传导措施的效用，并将为SFTN提供一个新的客观和敏感的生物标志物。因此，概述的研究将大大提高现有的各种毒性神经病动物模型的实用性，包括与化疗相关的动物模型，并将为与许多人类疾病（包括糖尿病、艾滋病和遗传性神经病）相关的神经损伤的临床和临床前评估提供新的工具。公共卫生关系：这些研究将为小直径有髓和无髓轴突（A4和C纤维）功能中毒素诱导或疾病相关缺陷提供新的生物标志物。虽然这些轴突在处理疼痛、热敏感性和自主神经功能中起着关键作用，并且是大多数神经中的主要纤维类型，但它们通过现有技术测量得很差，因此研究不足。如果成功，概述的研究将大大提高各种毒性神经病（包括与化疗相关的毒性神经病）的现有动物模型的实用性，并将为与许多人类疾病（包括糖尿病，艾滋病和遗传性神经病）相关的神经损伤的临床和临床前评估提供新的工具。