Magnetic Targeting to a Modulator of Metabolism in the Olfactory Bulb

 描述(申请人提供)：肥胖已成为全世界的流行病，缓解肥胖的疗法尚未成功开发。近年来，嗅觉和代谢功能之间的关系变得越来越明显。各种代谢信号通过调节嗅球内的信号来改变嗅觉行为。同样，小鼠电压门控离子通道Kv1.3的基因靶标缺失导致OB初级投射神经元的兴奋性增加，并伴随着OB依赖新陈代谢的增加。这项提议的主要目标是确定OB中Kv1.3的靶向干扰是否可以改变新陈代谢，进而被证明是肥胖和其他代谢紊乱的潜在治疗靶点。这项建议的方法是高度交叉的，应用了电生理学(异源表达和传统切片)、药理学、纳米颗粒技术、药物输送(外科手术植入渗透压微型泵和鼻腔给药)、药物追踪(磁共振成像)和代谢评估。该建议的具体目的基于两个假设：1)在Kv1.3抑制剂中添加磁性纳米颗粒将导致在施加磁场期间嗅球内滞留的浓度增加，并将允许通过磁共振成像跟踪药物载体在大脑中的分布；2)有针对性地降低Kv1.3电导将改变嗅球的电活动，从而增加新陈代谢和减轻体重。该提案中的工作将开发一种纳米药物载体，并将使用膜片钳电生理学来确定其药理特性。在将药物载体传递给小鼠之后，将进行体内磁共振成像，以便可以确认和优化针对OB的靶向传递。为了确定药物载体对代谢功能的影响，动物将被安置在定制的代谢室中，同时进行药物输送。这项工作旨在确定靶向干扰Kv1.3是否可以改变新陈代谢，以及开发一种靶向OB的药物输送方式。

 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.