Novel Theranostic Approaches to Identify and Treat Tinnitus Using Functionalized Nanoparticles

使用功能化纳米粒子识别和治疗耳鸣的新治疗诊断方法

• 批准号: 9313977
• 负责人: Magnus Bergkvist
• 金额: $ 13.75万
• 依托单位: SUNY POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313977
• 关键词: Abate; Achievement; Acoustic Stimulation; Address; Adult; Adverse effects; Anatomy; Animal Model; Animals; Antibodies; Area; Attenuated; Auditory; Auditory area; Auditory system; Benchmarking; Binding; Binding Proteins; Biological; Blast Cell; Blood - brain barrier anatomy; Brain; Brain Concussion; Brain region; Capsid; Cells; Cochlear nucleus; Complement; Complex; Contrast Media; Custom; Detection; Development; Diagnosis; Diagnostic; Disabled Persons; Dose; Drug Delivery Systems; Engineering; Evaluation; Exhibits; Exposure to; Fluorescence; Foundations; Frozen Sections; Future; Genes; Goals; Health; Hearing; Histologic; Hyperactive behavior; Image; Imagery; In Vitro; Individual; Inferior Colliculus; Injection of therapeutic agent; LDL-Receptor Related Protein 1; Laboratories; Magnetic Resonance Imaging; Measurement; Microscopy; Molecular; Nanotechnology; Neuraxis; Neurons; Neurosciences; Noise; Peptides; Perception; Peripheral; Pharmaceutical Preparations; Physiological; Proteins; Research; Research Personnel; Resources; Science; Site; Solid; Specificity; Sprague-Dawley Rats; Surface; Symptoms; System; Testing; Therapeutic; Time; Tinnitus; United States; Universities; Weight; Western Blotting; Work; auditory pathway; base; biological research; brain tissue; college; design; differential expression; driving force; falls; fluorophore; in vivo; innovation; interest; nanomaterials; nanoparticle; nanoscale; nanotheranostics; novel; novel strategies; overexpression; receptor binding; relating to nervous system; research facility; targeted delivery; theranostics

DESCRIPTION (provided by applicant): In the United States, about 50 million individuals suffer from tinnitus (perception of sound without overt acoustic stimulation), with circa 3 million people that are disabled and require treatment. Unfortunately, current treatment options for tinnitus are often ineffective and produce inconsistent and sometimes disappointing results. New and innovative approaches for diagnosis and treatment of tinnitus are urgently needed. Here, we introduce a novel concept for tinnitus research and abatement based on the hypothesis that over-expression of genes within brain regions with hyperactive neuronal activity associated with tinnitus can be identified and targeted using multifunctional capsid-based nanoparticles. The effort proposed here leverage a multifunctional capsid-based nanoparticle platform and represents the initial step toward our long-term goal to establish a nanoparticle-based platform to localize and treat tinnitus by attenuating hyperactive neural activity. We will ) evaluate whether nanoparticles can localize to specific targets in vitro and in vivo and ii) optimize the design for ideal localization within the brain and transport across the blood-brain-barrier (BBB) with negligible side effects. Here we seek to evaluate the feasibility of using nanoparticles for in vivo use and establish a solid foundation where future work will enable more in-depth studies using animal models of tinnitus. Specific Aim 1. To establish targeting of specific proteins within the inferior colliculus (IC) using custom-fabricated nanoparticles. Nanoparticles (NPs) will be designed to target proteins demonstrated to be differentially expressed in areas with tinnitus related hyperactivity. Adult Sprague-Dawley rats will be used to evaluate targeting specificity of the NPs. NPs decorated with antibodies that bind receptors in active neurons and loaded with fluorophore will be used for visualization during histological assessment. Two approaches to validate the specificity of NP binding are used: 1. Western blotting will be used to establish that the NPs are capable of binding the protein-of-interest isolated from the IC. This assessment will include, exposure to i) NPs modified with the specific antibody, ii) NPs without the antibody and iii) antibody alone. 2. Microscopy will be used to verify NP binding to the protein of interest in native IC cells. NPs loaded with a fluorescent tag will be localized to quantify differences in NP distribution within and across i) specific subdivisions of the IC ii) other auditory brain regions, as well as, iii) non-auditory brain region. Specific Aim 2. To optimize dose, localization, and transport of MRI detectable custom fabricated nanoparticles across the BBB. Adult Sprague-Dawley rats will be given a systemic injection of custom- designed NPs. They will be modified with a short peptide that facilitates BBB transport (through LPR-1). At multiple time points following injection, nanoparticles with a paramagnetic core and a conjugated fluorescent tag, will be localized: 1. with T1-weighted MRI and 2. cross-validated by fluorescence-based microscopy using frozen sections.

描述（由申请人提供）：在美国，大约有5000万人患有耳鸣（没有明显声音刺激的声音感知），其中约有300万人