Generation and characterization of in vivo models of Small Fiber Neuropathy

小纤维神经病体内模型的生成和表征

• 批准号: 9040028
• 负责人: Stephen Waxman
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9040028
• 关键词: Address; Adult; Affect; Age; Aging; Alcoholism; Autoimmune Diseases; Autonomic Dysfunction; Axon; Behavioral; Burn injury; Carbamazepine; Cells; Chimera organism; Cloning; Contracts; Custom; Development; Diabetes Mellitus; Disease; Dysautonomias; Electrophysiology (science); Exhibits; Fiber; Funding; Future; Generations; Genes; Goals; HIV; HIV Infections; Hand; Health; Human; Idiopathic Neuropathy; In Vitro; Incidence; Inflammatory; Knock-in Mouse; Laboratories; Length; Link; Mechanics; Medical; Methods; Molecular; Mus; Mutation; Nerve Fibers; Neurites; Neurodegenerative Disorders; Neurons; Neuropathy; Numbness; Pain; Pathway interactions; Patients; Peripheral Nerves; Phenotype; Population; Prevalence; Refractory; Research Project Grants; Sensory; Services; Sodium Channel; Sodium Channel Blockers; Swelling; Symptoms; Testing; Toxin; United States; Variant; Veterans; Visceral pain; agent orange; appendage; axonal degeneration; base; biophysical properties; cost; density; design; foot; gain of function; in vivo Model; mouse model; neoplastic; novel therapeutic intervention; patch clamp; proband; public health relevance; spontaneous pain; vector; voltage; Address; Adult; Affect; Age; Aging; Alcoholism; Autoimmune Diseases; Autonomic Dysfunction; Axon; Behavioral; Burn injury; Carbamazepine; Cells; Chimera organism; Cloning; Contracts; Custom; Development; Diabetes Mellitus; Disease; Dysautonomias; Electrophysiology (science); Exhibits; Fiber; Funding; Future; Generations; Genes; Goals; HIV; HIV Infections; Hand; Health; Human; Idiopathic Neuropathy; In Vitro; Incidence; Inflammatory; Knock-in Mouse; Laboratories; Length; Link; Mechanics; Medical; Methods; Molecular; Mus; Mutation; Nerve Fibers; Neurites; Neurodegenerative Disorders; Neurons; Neuropathy; Numbness; Pain; Pathway interactions; Patients; Peripheral Nerves; Phenotype; Population; Prevalence; Refractory; Research Project Grants; Sensory; Services; Sodium Channel; Sodium Channel Blockers; Swelling; Symptoms; Testing; Toxin; United States; Variant; Veterans; Visceral pain; agent orange; appendage; axonal degeneration; base; biophysical properties; cost; density; design; foot; gain of function; in vivo Model; mouse model; neoplastic; novel therapeutic intervention; patch clamp; proband; public health relevance; spontaneous pain; vector; voltage

DESCRIPTION (provided by applicant): Small fiber neuropathy (SFN) is a neurodegenerative disorder that is characterized by a loss of unmyelinated C-, small myelinated Ad- and autonomic fibers, and is associated with sensory and autonomic dysfunctions, including burning, pin-prick and lancinating pain and autonomic symptoms, which are often refractory to treatment. SFN has been linked to multiple causes, including diabetes, alchoholism, toxins, including Agent Orange, HIV, anti-neoplastic treatments, and autoimmune disorders, but a substantial percentage of SFN are idiopathic, with no apparent cause. We have recently demonstrated the presence of gain-of-function variants in sodium channel Nav1.7 in nearly 30% of patients with SFN and no other apparent cause. However, the molecular cascade leading to small fiber loss and onset of pain associated with the gain- of-function variants in Nav1.7, or any of the multiple causes linked to SFN, is not yet understood. The proposed Small Project is designed to develop an in vivo model of small fiber neuropathy by creating knock-in mice with heterozygous insertion of a human gain-of-function variant in the Scn9a (Nav1.7) gene at the Scn9a allelle. Multiple gain-of-function variants in Nav1.7 have been found in patients with idiopathic SFN, and our electrophysiological and morphological studies of two variants (I228M and G856M) as exceptionally promising candidates in which to pursue generation of in vivo models. For our studies, knock-in mice are generated and phenotypically characterized by morphological, whole-cell patch clamp and behavioral methods. In future studies not funded by this proposal, the knock-in mice will serve as valuable platforms in which to perform mechanistic studies to determine the molecular pathway(s) leading to axonal degeneration and the onset of sensory and autonomic dysfunction in SFN. It is also anticipated that the development of the in vivo models will allow us to identify and test novel therapeutic approaches to minimize axonal degeneration, and the sensory and autonomic dysfunctions associated with fiber loss, in human small fiber neuropathy.

描述（由申请人提供）： 小型纤维神经病（SFN）是一种神经退行性疾病，其特征是丧失了无髓鞘的C-，小骨髓的AD和自主纤维，并且与感觉和自主性功能障碍有关，包括燃烧，刺激性和耐腹膜，疼痛和自动症状，通常是经常进行治疗的，这些症状通常是拒绝进行治疗。 SFN与多种原因有关，包括糖尿病，藻类，毒素，包括橙色，艾滋病毒，抗肿瘤治疗和自身免疫性疾病，但SFN很大一部分是特发性的，没有明显的原因。 最近，我们证明了近30％的SFN患者且没有其他明显原因的钠通道NAV1.7中有功能的变异。 然而，尚不清楚导致纤维损失小的纤维损失和疼痛发作的分子级联反应与NAV1.7中的功能变体或与SFN相关的任何多个原因中的任何一个。 该提出的小型项目旨在通过在SCN9A Allelle的SCN9A（NAV1.7）基因中杂合插入杂合插入杂合插入的小鼠，从而开发出小纤维神经病的体内模型。 在特发性SFN的患者中发现了NAV1.7的多种功能变异，我们对两种变体（I228M和G856M）的电生理和形态学研究是非常有希望的候选者，可以在其中追求体内生成的生成。在我们的研究中，敲入小鼠是由形态学，全细胞斑块夹和行为方法产生和表型的。 在未来的研究中不是由该提案资助的研究中，敲入小鼠将用作有价值的平台，在其中进行机械研究以确定分子途径，从而导致轴突变性以及SFN的感觉和自主神经功能障碍的发作。 还可以预料，体内模型的发展将使我们能够识别和测试新型的治疗方法，以最大程度地减少轴突变性，以及在人类小纤维神经病中与纤维损失相关的感觉和自主性功能障碍。