TrkB.T1 as a Genetic Disease Modifier of Muscular Dystrophy

TrkB.T1 作为肌营养不良症的遗传疾病修饰剂

• 批准号: 7853645
• 负责人: SUSAN G DORSEY
• 金额: $ 110.81万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7853645
• 关键词: Acute; Age; Becker Muscular Dystrophy; Biopsy; Biopsy Specimen; Brain-Derived Neurotrophic Factor; Caring; Cells; Cessation of life; Clinical; Clinical Research; Complex; Coupling; Defect; Disease; Disease Progression; Distal; Duchenne muscular dystrophy; Dystrophin; Event; Facioscapulohumeral; Family; Fiber; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Government; Health Care Costs; Hereditary Disease; Inherited; Injury; Investigation; Knockout Mice; Ligands; Limb structure; Mediating; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscle Proteins; Muscle Weakness; Muscle function; Muscular Dystrophies; Natural regeneration; Neonatal; Neurotrophic Tyrosine Kinase Receptor Type 2; Pathology; Patients; Performance; Physiological; Process; Protein Isoforms; RNA Splicing; Regulation; Research Personnel; Research Priority; Resistance; Role; Sampling; Severity of illness; Signal Transduction; Skeletal Muscle; Staging; Tetanus Helper Peptide; Time; Tissues; Transforming Growth Factor beta; Transgenic Mice; Up-Regulation; Work; base; clinical phenotype; gain of function; gene therapy; improved; in vivo; mdx mouse; mouse model; muscle degeneration; muscle regeneration; muscle strength; neuromuscular; new therapeutic target; postnatal; prevent; public health relevance; receptor; repaired; repository; research study; therapeutic target; ward

DESCRIPTION (provided by applicant): The muscular dystrophies are complex genetic diseases characterized by inherited or sporadic defects in genes that encode muscle proteins. Although Duchenne (DMD), Becker, limb girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss are the most common muscular dystrophies, the total number of diseases characterized as muscular dystrophies exceeds thirty (MD-CARE_Act, 2008). Common to all of the muscular dystrophies is progressive skeletal muscle weakness and the death of muscle cells and tissue. Although the genetic basis for most of the dystrophies is known, a disease cure may still be years away. This fact has increased the research priority mandate from researchers, family support organizations (G¿nter Scheuerbrandt, 2008) and the government (MD-CARE_Act, 2008) to identify critical "downstream" events in the dystrophic process that can be therapeutically targeted to halt or slow the disease progression until a genetic (gene therapy) cure is realized. Transforming Growth Factor beta (TGF-() signaling is pathogenic in dystrophy (Chen et al., 2005). Recent work by our group showed that antagonizing TGF-( normalizes muscle repair and restores muscle function in the well-described mdx mouse model of muscular dystrophy (Cohn et al., 2007). To identify critical downstream transcriptional events following increased TGF-( signaling, we generated a tet-repressible muscle-specific TGF-( transgenic mouse and we find that over-expression of TGF-( causes muscle weakness (Hoffman and Chen, unpublished). In related preliminary studies examining gene expression in clinical DMD muscle biopsy samples we show that the truncated form of the Brain-derived Neurotrophic Factor (BDNF) receptor, trkB.T1, but not other trkB isoforms, is highly associated with TGF-( expression (Hoffman et al., unpublished). Further investigation revealed that genetic deletion of trkB.T1 (Dorsey et al., 2006) results in a gain-of-function in neuromuscular performance, increased muscle contractility and resistance to eccentric muscle injury (Dorsey and Ward, unpublished). Complementary gene expression studies showed that TGF-( and its receptor were downregulated in trkB.T1-/- muscle. An intercross between trkB.T1-/- and mdx mice to reduce trkB.T1 expression in vivo resulted in a complete rescue of dystrophy-associated loss of skeletal muscle contractility (Dorsey and Ward, unpublished), similar to targeting TGF-( (Cohn et al., 2007). We hypothesize that trkB.T1 may be a significant disease modifier of muscular dystrophy and could represent a novel therapeutic target for its treatment. PUBLIC HEALTH RELEVANCE: Muscular dystrophy is a disease that causes significant muscle weakness that gets worse over time. Although we know about the genetic causes of the disease, we still do not have ways to slow down muscle weakness or make muscles stronger once they become weak. From our preliminary studies, we have an idea that two molecules that function in muscle cells to regulate muscle strength might be able to be manipulated to improve muscle function in patients with muscular dystrophy. This study will try to figure out why these two molecules may be possible therapeutic targets. Our goal is to prevent, improve, or restore muscle function in patients with muscular dystrophy.

描述(申请人提供)：肌肉营养不良症是一种复杂的遗传性疾病，其特征是编码肌肉蛋白的基因遗传或零星缺陷。虽然Duchenne(DMD)、Becker、肢带、先天性、面肩-肱骨、肌强直、眼咽、远端和Emery-Dreifuss是最常见的肌营养不良症，但以肌营养不良为特征的疾病总数超过30种(MD-CARE_Act，2008)。所有肌肉营养不良的共同之处是进行性骨骼肌无力和肌肉细胞和组织的死亡。虽然大多数营养不良的遗传基础是已知的，但疾病的治愈可能仍需数年时间。这一事实增加了研究人员、家庭支持组织(G‘nter Scheuerbrandt，2008)和政府(MD-CARE_Act，2008)的研究优先任务，以确定营养不良过程中的关键“下游”事件，这些事件可以作为治疗目标，以阻止或减缓疾病的进展，直到实现基因(基因疗法)治愈。转化生长因子β信号在营养不良中是致病的(Chen等人，2005年)。我们团队最近的工作表明，在众所周知的肌营养不良MDX小鼠模型中，拮抗转化生长因子-1可以使肌肉修复正常化并恢复肌肉功能(Cohn等人，2007年)。为了确定随着转化生长因子-()信号的增加而发生的关键下游转录事件，我们产生了一个可抑制的肌肉特异性转化生长因子-(转基因)小鼠，我们发现转化生长因子-()的过度表达会导致肌肉无力(Hoffman和Chen，未发表)。在检测临床DMD肌肉活检样本中基因表达的相关初步研究中，我们发现脑源性神经营养因子(BDNF)受体trkB.T1的截断形式，而不是其他TrkB亚型，与转化生长因子-1的表达高度相关(Hoffman等，未发表)。进一步的研究表明，trkB.T1的基因缺失(Dorsey等人，2006年)导致神经肌肉功能增强、肌肉收缩能力增强和对偏心性肌肉损伤的抵抗力(Dorsey和Ward，未发表)。互补基因表达研究表明，在trkB.T1-/-肌肉中，转化生长因子-α及其受体表达下调。TrkB.T1-/-与MDX小鼠之间的交叉杂交以降低trkB.T1在体内的表达导致了营养不良相关的骨骼肌收缩能力丧失的完全挽救(Dorsey和Ward，未发表)，类似于靶向转化生长因子-1(Cohn等人，2007年)。我们假设trkB.T1可能是肌营养不良症的一个重要的疾病修饰物，并可能代表其治疗的新的治疗靶点。 与公共卫生相关：肌肉营养不良症是一种会导致严重肌肉无力的疾病，随着时间的推移，这种疾病会变得更严重。尽管我们知道这种疾病的遗传原因，但我们仍然没有办法减缓肌肉虚弱的速度，或者在肌肉变得虚弱时让肌肉变得更强壮。从我们的初步研究中，我们有了一个想法，即两个在肌肉细胞中调节肌肉力量的分子可能能够被操纵来改善肌肉营养不良患者的肌肉功能。这项研究将试图找出为什么这两个分子可能是治疗的靶点。我们的目标是预防、改善或恢复肌营养不良症患者的肌肉功能。