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.

脊髓小脑性共济失调 1 型 (SCA1) 是一种进行性神经退行性疾病，由蛋白质 ATXN1 中的聚谷氨酰胺扩增。在描绘早期机制的过程中潜在的神经变性，我们意外地发现 ATXN1 直接调节血管生成和神经营养细胞因子 VEGF 的表达，并且 VEGF 水平异常小鼠大脑中 SCA1 水平较低，会产生病理后果。从那以后我们发现，交付重组 VEGF 对已充分表征的 SCA1 敲入小鼠 (SCA1154Q/2Q；SCA1154Q/2Q； Q=谷氨酰胺），现有最精确的 SCA1 小鼠模型。然而，也存在一些挑战开发重组 VEGF 作为一种疗法。在这里，我们建议以我们最近的工作为基础开发一种易于合成的 VEGF 模拟颗粒，具有更大的潜力与神经元和内皮细胞中的 VEGF 受体结合，以维持神经血管健康 SCA1。目标是为 SCA1 设计一流的纳米疗法。