Magnetic Targeting to a Modulator of Metabolism in the Olfactory Bulb

磁靶向嗅球代谢调节剂

• 批准号: 9051094
• 负责人: Austin Schwartz
• 金额: $ 3.83万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-17 至 2018-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9051094
• 关键词: Animals; Behavior; Biological; Body Weight; Brain; Cues; Custom; Diet; Dose; Drug Delivery Systems; Electrophysiology (science); Epidemic; Fatty acid glycerol esters; Feeding behaviors; Gated Ion Channel; Gene Targeting; Glucose; Homeostasis; Housing; Insulin; Laboratories; Lead; Magnetic Resonance Imaging; Magnetic nanoparticles; Magnetism; Maintenance; Metabolic; Metabolic Diseases; Metabolism; Methods; Mus; Nanotechnology; Neuromodulator; Neurons; Obesity; Operative Surgical Procedures; Pharmaceutical Preparations; Pharmacology; Potassium Channel; Property; Pump; Research; Role; Signal Transduction; Slice; Smell Perception; Specificity; System; Technology; Testing; Therapeutic; Work; base; biological research; design; drug distribution; implantation; improved; in vivo; inhibitor/antagonist; magnetic field; metabolic engineering; mitral cell; nanoparticle; novel; olfactory bulb; patch clamp; public health relevance; response; targeted delivery; therapeutic target; thermostability; vector; voltage

 DESCRIPTION (provided by applicant): Obesity has become an epidemic throughout the world and therapeutics to mitigate this have yet to be successfully developed. In recent years, the relationship between olfaction and metabolic function has become apparent. A variety of metabolic cues alter olfactory behavior by modulating signaling within the olfactory bulb (OB). Likewise, gene-target deletion in mice of the voltage-gated ion channel Kv1.3 yields increased excitability of the primary projection neurons in the OB and a concomitant OB dependent increase in metabolism. The PRIMARY GOAL of this proposal is to determine if targeted disruption of Kv1.3 in the OB can alter metabolism, in turn proving to be a potential therapeutic target for obesity and other metabolic disorders. The METHODS of this proposal are highly interdisciplinary, applying electrophysiology (heterologous expression and traditional slice), pharmacology, nanoparticle technology, drug delivery (surgical implantation of osmotic mini-pumps and intranasal delivery), drug tracking (magnetic resonance imaging), and metabolic assessment. The SPECIFIC AIMS of this proposal are based upon two HYPOTHESES: 1) Addition of an magnetic nanoparticle to a Kv1.3 inhibitor will lead to increased concentrations retained within the olfactory bulb during application of magnetic field and will allow for trackingof the drug vector's distribution throughout the brain with magnetic resonance imaging, and 2) A targeted reduction of Kv1.3 conductance will alter electrical activity in the olfactory bulb, in tun increasing metabolism and reducing body weight. The work in this proposal will develop a nanoparticle drug vector and its pharmacological properties will be determined using patch-clamp electrophysiology. Following delivery of the drug vector to mice, in-vivo magnetic resonance imaging will be performed such that targeted delivery towards the OB can be confirmed and optimized. To determine the drug vector's effect on metabolic function, animals will be housed in custom engineered metabolic chambers while drug delivery is being performed. This work aims to both determine if targeted disruption of Kv1.3 can alter metabolism as well as develop a means of targeted drug delivery towards the OB.

 描述（由申请人提供）：肥胖已成为世界范围内的流行病，缓解肥胖的治疗方法尚未成功开发。近年来，嗅觉与代谢功能之间的关系越来越明显。多种代谢信号通过调节嗅球（OB）内的信号而改变嗅觉行为。同样地，在小鼠中，电压门控离子通道Kv1.3的基因靶向缺失产生OB中初级投射神经元的兴奋性增加以及伴随的OB依赖性代谢增加。该提案的主要目标是确定OB中Kv1.3的靶向破坏是否可以改变代谢，从而证明是肥胖和其他代谢紊乱的潜在治疗靶点。该提案的方法是高度跨学科的，应用电生理学（异源表达和传统切片）、药理学、纳米颗粒技术、药物递送（渗透微型泵的手术植入和鼻内递送）、药物追踪（磁共振成像）和代谢评估。本提案的具体目标基于两个假设：1）将磁性纳米颗粒添加到Kv1.3抑制剂中将导致在施加磁场期间保留在嗅球内的浓度增加，并且将允许用磁共振成像跟踪药物载体在整个大脑中的分布，和2）Kv1.3电导的靶向降低将改变嗅球中的电活动，从而增加代谢并减轻体重。本研究将开发一种纳米药物载体，并利用膜片钳电生理学方法测定其药理学特性。在将药物载体递送至小鼠后，将进行体内磁共振成像，使得可以确认和优化朝向OB的靶向递送。为了确定药物载体对代谢功能的影响，在进行药物递送的同时，将动物圈养在定制的工程代谢室中。这项工作旨在确定Kv1.3的靶向破坏是否可以改变代谢，以及开发一种靶向药物递送到OB的方法。