VEGF-Mimetic Supramolecular Nanoparticles for Treating Spinocerebellar Ataxia Type 1

VEGF 模拟超分子纳米颗粒用于治疗 1 型脊髓小脑共济失调

基本信息

批准号：
10578485
负责人：
Puneet Opal
金额：
$ 36.13万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578485
关键词：
Ablation Affect Autopsy Behavioral Benchmarking Biological Assay Brain Brain Stem CAG repeat Central Nervous System Cerebellar Ataxia Cerebellar degeneration Cerebellum Cerebrospinal Fluid Chemistry Clinic Confocal Microscopy Disease Disease model Drug Kinetics Elements Endothelial Cells Endothelial Growth Factors Receptor Engineering Environment Exhibits Formulation Freedom Gadolinium Glutamine Goals Health Hippocampus Histologic Human In Vitro Inductively Coupled Plasma Mass Spectrometry Inflammation Inherited Injections Intellectual Property Knock-in Mouse Label Length Magnetic Resonance Imaging Measures Medicine Metals Methods Microscopy Modeling Monitor Motor Mus Nanostructures Nature Nerve Degeneration Neurodegenerative Disorders Neurons Pathologic Patients Penetration Phase Phenotype Physiological Pre-Clinical Model Process Property Proteins Recombinant Vascular Endothelial Growth Factor Repression Resolution Sampling Spatial Distribution Spinal Cord Symptoms Techniques Technology Testing Therapeutic Therapeutic Agents Time Toxic effect Translating Trinucleotide Repeat Expansion Tumorigenicity Type 1 Spinocerebellar Ataxia VEGFA gene Vascular Endothelial Growth Factors Visualization Work angiogenesis aqueous ataxin-1 autosome comparative efficacy cost cytokine design disease phenotype efficacy evaluation experience experimental study gain of function human model immunogenic improved in vivo laser spectrometry manufacture middle age mimetics mouse model mutant nano nanoparticle nanotherapy neurovascular novel particle peptide amphiphiles peptidomimetics polyglutamine treatment strategy

项目摘要

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a polyglutamine expansion in the protein ATXN1. In the course of delineating early mechanisms underlying neurodegeneration, we made the unexpected discovery that ATXN1 directly regulates the expression of the angiogenic and neurotrophic cytokine VEGF and that VEGF levels are abnormally low in the SCA1 mouse brain with pathologic consequences. We have since discovered that delivering recombinant VEGF is therapeutic in the well-characterized SCA1 knock-in mouse (SCA1154Q/2Q; Q=glutamine), the most precise existing mouse model of SCA1. However, there are several challenges with developing recombinant VEGF as a therapy. Here we propose to build upon our recent work developing a VEGF-mimetic particle that could be readily synthesized with a greater potential to engage VEGF receptors in both neurons and endothelial cells to maintain neurovascular health in SCA1. The goal is to engineer a first-in-class nanotherapy for SCA1.

1型脊髓脑性共济失调（SCA1）是一种由A引起的进行性神经退行性疾病蛋白质ATXN1中的聚谷氨酰胺扩展。在描述早期机制的过程中潜在的神经变性，我们意外发现ATXN1直接调节血管生成和神经营养性细胞因子VEGF的表达，而VEGF水平异常为 SCA1小鼠脑的低点具有病理后果。从那以后，我们发现交付重组VEGF在特征良好的SCA1敲入小鼠中具有治疗性（SCA1154Q/2Q； Q =谷氨酰胺），这是SCA1的最精确的鼠标模型。但是，有几个挑战将重组VEGF作为一种疗法发展。在这里，我们建议以我们最近的工作为基础开发一个可以容易合成的VEGF模拟粒子，具有更大的潜力在神经元和内皮细胞中吸引VEGF受体，以维持神经血管健康 SCA1。目的是设计SCA1的第一类纳米疗法。