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Mechanisms of neuromuscular degeneration in SBMA

SBMA 神经肌肉变性的机制

基本信息

批准号：
10290437
负责人：
ANDREW P LIEBERMAN
金额：
$ 55.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10290437
关键词：
1 year old AR gene Androgen Receptor Antisense Oligonucleotides Atrophic Biochemical Genetics Biological Assay Cell Differentiation process Cells Chronic Complement Data Defect Development Disease Disease model Exercise Tolerance Foundations Future Gene Targeting Genetic Transcription Glutamine Goals Histologic Hormones Human Laboratories Longevity Metabolic Modeling Molecular Chaperones Motor Neuron Disease Motor Neurons Mus Muscle Weakness Muscular Atrophy Neuromuscular Diseases Nuclear Translocation Pathogenesis Pathogenicity Pathology Patients Peripheral Phenotype Public Health Publishing Research Design Skeletal Muscle Spinal Spinal Cord Testing Time Tissues Toxic effect Translating Ubiquitination Work base cell type chaperone machinery experimental study functional restoration human embryonic stem cell line in vivo induced pluripotent stem cell innovation insight knock-down men motor neuron degeneration neuromuscular neuromuscular system neuron loss novel novel therapeutic intervention overexpression polyglutamine proteotoxicity public health relevance receptor receptor expression skeletal muscle wasting small molecule spinal and bulbar muscular atrophy targeted treatment therapy development transcription factor treatment duration uptake

项目摘要

ABSTRACT Spinal and bulbar muscular atrophy (SBMA) is a degenerative disorder of the neuromuscular system caused by a CAG/glutamine tract expansion in the androgen receptor (AR) gene. The polyglutamine AR (polyQ AR) undergoes hormone-dependent nuclear translocation and unfolding, steps that are essential to toxicity and to the development of progressive muscle weakness in men. Although it was long considered that lower motor neurons are the primary targets of degeneration in SBMA, recent studies from our laboratory and others have established the importance of peripheral polyQ AR expression in disease. This work highlights a central contribution of polyQ AR expression in skeletal muscle to weakness and atrophy. Based on these findings, we have developed an innovative model of SBMA pathogenesis in which degeneration of the neuromuscular system begins with toxic effects in skeletal muscle and progresses over time to involve spinal motor neuron degeneration. Here, we propose to test this model of disease pathogenesis in gene targeted mice (AR113Q mice) expressing polyQ AR at endogenous levels and in appropriate cell types. The objective of this application is to experimentally test our novel model of disease pathogenesis. This model forms our central hypothesis and is supported by a rigorous foundation of published and preliminary data. Here, we will use two complementary approaches to test our central hypothesis: First, we will use antisense oligonucleotides (ASOs) to knock-down expression of polyQ AR selectively in peripheral tissues or CNS of symptomatic AR113Q mice and determine effects on late onset motor neuron degeneration. Second, we will restore function of a critical transcriptional regulator in skeletal muscle that contributes to SBMA skeletal muscle atrophy and then determine the extent to which this influences the AR113Q phenotype, including motor neuron degeneration. These aims will be complemented by studies designed to leverage the endogenous cellular machinery that regulates polyQ AR degradation in order to eliminate proteotoxicity in disease relevant human cells. We will use biochemical, genetic, and histological assays to establish beneficial effects of AR targeted ASOs administered to symptomatic AR113Q mice (Aim 1), determine the extent to which increased MEF2 function rescues the AR113Q phenotype (Aim 2), and establish effects of targeting the Hsp90/Hsp70 chaperone machinery in SBMA models (Aim 3). These studies are expected to experimentally test our proposed model of disease pathogenesis and provide a strong foundation for developing targeted therapies to treat SBMA patients.

摘要