Androgen Targets in a Simple Behavioral System

简单行为系统中的雄激素目标

基本信息

批准号：
8963558
负责人：
CYNTHIA L JORDAN
金额：
$ 33.03万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8963558
关键词：
Acetylcholine Action Potentials Adult Affect American Androgen Antagonists Androgen Receptor Androgens Animals Bathing Behavioral Bicalutamide Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor Calcium Cells Cessation of life Chloride Channels Cholinergic Receptors Clinical Trials Conotoxin Cytoskeletal Modeling Cytoskeletal Proteins Data Defect Denervation Dependence Disease Disease model Dissociation Employee Strikes Exhibits FDA approved Fiber Flutamide Functional disorder Gene Expression Genes In Vitro Ion Channel Kennedy Syndrome Leuprolide Measures Mediating Membrane Messenger RNA Microfilaments Modeling Molecular Motor Motor Neurons Mus Muscle Muscle Contraction Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Mutate Myotonic Dystrophy Neonatal Neurodegenerative Disorders Neuromuscular Diseases Paper Patients Peripheral Phenotype Physiological Process Property Protein Isoforms Publishing Reporting Research Personnel Resistance Rest Role Safety Skeletal Muscle Sodium Channel Spinal Synapses System Testing Testosterone Transcript Transgenes Transgenic Mice Transgenic Organisms Woman cellular targeting combat disease phenotype effective therapy extracellular falls in vivo innovation male men middle age motor disorder mouse model mutant nerve supply neuromuscular neuromuscular system novel overexpression public health relevance recombinase response synaptic function

项目摘要

DESCRIPTION (provided by applicant): A long-standing and significant barrier to understanding the mechanisms behind Kennedy disease (KD) is the assumption that the agent of disease (a mutated androgen receptor (AR)) acts directly in motoneurons to cause their death. While skeletal muscle are also affected in KD, muscle atrophy and weakness was attributed to a loss of innervation; i.e., effects of disease on muscle was assumed to have a neurogenic cause. A transgenic (tg) mouse model developed to identify the cells that androgens act on to drive sexual differentiation of a neuromuscular system led to the serendipitous discovery that AR acts in muscle fibers (not motoneurons) to trigger KD. This finding has prompted a major paradigm shift in the field. Mouse models developed by other investigators since this discovery also conclude AR acts directly in muscle to cause KD, questioning whether AR in motoneurons has any role in this disease. The current proposed Aims continue to build on this new appreciation for muscle as a key player in KD, using an innovative systems approach and cross-model comparisons to identify critical mechanisms in muscle that directly impart disease to the muscle and indirectly to the motoneurons. Aim 1 will extend pilot data using qPCR to further characterize the expression of neonatal isoforms of critical membrane channels and cytoskeletal proteins that control muscle contractile properties in diseased adult KD muscle. Aim 2 will use classic physiological approaches to determine whether muscles are functionally denervated. Aim 3 will continue efforts to test FDA approved AR antagonists as immediately available treatment options for KD patients by testing the AR antagonist bicalutamide which does not readily cross the blood-brain barrier in three KD mouse models. Aim 4 will directly test whether brain-derived neurotrophic factor (BDNF) produced in skeletal muscle mediates motor dysfunction in KD using two in vivo complimentary approaches, 1) reversing a disease-related deficit in muscle BDNF via expression of a BDNF transgene in KD muscle and 2) disabling the endogenous BDNF gene in KD muscle. This last Aim takes advantage of floxed and cre recombinase mouse models that we have ready access to.

描述（由申请人提供）：理解肯尼迪病（KD）背后机制的一个长期存在的重大障碍是假设疾病的媒介（突变的雄激素受体（AR））直接作用于运动神经元导致其死亡。虽然骨骼肌也受到川崎病的影响，但肌肉萎缩和无力归因于神经支配的丧失；即，疾病对肌肉的影响被认为是由神经源性原因引起的。为识别雄激素作用于驱动神经肌肉系统性别分化的细胞而开发的模型导致了偶然的发现，即 AR 作用于肌肉纤维（而不是运动神经元）以引发 KD。这一发现促使了该领域的重大范式转变。自这一发现以来，其他研究人员开发的模型也得出结论，AR 直接作用于肌肉，导致 KD，质疑运动神经元中的 AR 是否在这种疾病中发挥作用。目前提出的目标继续建立在对肌肉作为关键参与者的新认识的基础上。在 KD 中，使用创新的系统方法和跨模型比较来确定肌肉中直接将疾病传递给肌肉并间接传递给运动神经元的关键机制，目标 1 将使用 qPCR 扩展试点数据，以进一步表征关键新生儿亚型的表达。 Aim 2 将使用经典的生理学方法来确定肌肉是否功能失神经，Aim 3 将继续努力测试 FDA 批准的 AR。通过在三种 KD 小鼠模型中测试 AR 拮抗剂比卡鲁胺（bicalutamide）不易穿过血脑屏障，Aim 4 将直接测试骨骼肌中产生的脑源性神经营养因子（BDNF）是否介导，从而将拮抗剂作为 KD 患者立即可用的治疗选择。使用两种体内补充方法治疗川崎病的运动功能障碍，1）通过在川崎病肌肉中表达 BDNF 转基因来逆转肌肉 BDNF 的疾病相关缺陷，2）禁用内源性KD 肌肉中的 BDNF 基因利用了我们现成的 floxed 和 cre 重组酶小鼠模型。