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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.

脊髓小脑共济失调1型（SCA 1）是一种进行性神经退行性疾病，在蛋白质ATXN 1中的多聚谷氨酰胺扩增。在描绘早期机制的过程中，在研究潜在的神经退行性疾病时，我们意外地发现ATXN 1直接调节了血管生成和神经营养细胞因子VEGF的表达，以及VEGF水平异常在SCA 1小鼠脑中低，具有病理后果。后来我们发现，重组VEGF在充分表征的SCA 1敲入小鼠（SCA 1154 Q/2 Q; Q=谷氨酰胺），SCA 1的最精确的现有小鼠模型。然而，开发重组VEGF作为一种治疗方法。在此，我们建议在我们最近工作的基础上，开发一种VEGF模拟颗粒，其可以容易地合成，具有更大的潜力，参与神经元和内皮细胞中的VEGF受体，以维持神经血管健康， SCA1.我们的目标是为SCA 1设计一流的纳米疗法。