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Modulation of Jagged1/Pitpna in DMD as a means of therapy

DMD 中 Jagged1/Pitpna 的调节作为治疗手段

基本信息

批准号：
10666524
负责人：
LOUIS M KUNKEL
金额：
$ 38.94万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666524
关键词：
Affect Bioinformatics Blood flow Canis familiaris Cardiopulmonary Cell Line Cell model Cessation of life Clinical Research Complement Control Animal DNA Sequence Alteration Data Disease Disease Progression Down-Regulation Duchenne muscular dystrophy Dystrophin Evaluation Exhibits Failure Fibrosis Gene Expression Profiling Generations Genes Genetic Genetic study Goals Grant Human In Vitro Injections Investigation Life Longevity Modeling Mus Muscle Muscle Cells Muscle function Muscular Atrophy Muscular Dystrophies Myoblasts Outcome PTEN gene Pathology Pathway interactions Patient-Focused Outcomes Patients Performance Phenotype Phosphatidylinositol Transfer Protein Predisposition Proliferating Proteins Proto-Oncogene Proteins c-akt Reading Frames Replacement Therapy Research Role Sarcolemma Signal Pathway Signal Transduction Skeletal Muscle Swimming Symptoms Terminator Codon Testing Therapeutic Transgenic Organisms Translations Viral Zebrafish adeno-associated viral vector candidate identification comparative disease-causing mutation efficacy evaluation exon skipping experimental study follow-up heart function improved in vivo inhibitor inhibitor therapy knock-down mRNA Expression mini-dystrophin mouse model muscle degeneration muscular structure overexpression pharmacologic premature prevent restoration targeted treatment therapeutic target treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Duchenne Muscular Dystrophy (DMD) is a degenerative muscle wasting disease caused by mutations in the dystrophin gene. The absence of dystrophin protein at the muscle sarcolemma results in increased muscle susceptibility to contraction-induced damage as well as dysregulation of secondary signaling pathways, many of which remain poorly understood. Despite advances in treatment strategies under investigation aimed at restoration of dystrophin expression including viral delivery of mini-dystrophin, read-through of translation stop codons, and exon skipping to restore the reading frame, there is no cure for DMD, and the identification of therapies that improve pathology independent of dystrophin would be of significant value to patients. In this vain, genetic modifiers of DMD are emerging as potential therapeutic targets. Our lab recently identified Jagged1 and Pitpna as genetic modifiers of DMD pathology in a Golden Retriever Muscular Dystrophy (GRMD) dog colony in which two exceptional “escaper” dogs exhibited a drastically milder phenotype than typical GRMD dogs despite being dystrophin-deficient. Normally, GRMD dogs show a severe phenotype similar to human DMD including early progressive muscle degeneration, fibrosis, and premature death often within the first 2 years of life due to cardiopulmonary failure. Gene expression analyses of the escaper dogs compared to severely affected GRMD dogs and control animals revealed that Jagged1 overexpression (OE) and decreased Pitpna expression were hallmarks of the mild phenotype, which including maintained ambulation and normal lifespan. In subsequent genetic studies of dystrophin-deficient zebrafish, we demonstrated that modulation of Jagged1 and Pitpna prevents manifestation of the dystrophic muscle phenotype, increases long-term survival, and improves swim performance. In primary myoblasts derived from normal and DMD patients, we also showed that Jagged1 overexpression and Pitpna inhibition impact AKT/PTEN signaling and improve myoblast fusion. Given this positive data, we will now extend our research of Jagged1 and Pitpna modulation into the well-characterized mdx5cv mouse model of DMD. We will also investigate genetic and pharmacological inhibition of PDE10A, which we have shown to elicit decreased Pitpna expression and improve dystrophic pathology in dystrophin-deficient zebrafish. The long-term goal in this project is to assess and validate the therapeutic potential of the genetic modifiers Jagged1 and Pitpna to ameliorate DMD pathology, and to identify a viable pharmacologic modulator to advance into clinical studies. To accomplish this, we will implement experiments in accordance to the following three specific aims: 1) Determine the effect of reduced Pitpna expression on dystrophic pathology in mdx5cv mice, 2) Characterize the functional role of Jagged1 overexpression in mdx5cv mice, and 3) Assess the therapeutic potential of PDE10A inhibition on dystrophic pathology in primary human muscle cells, zebrafish, and mouse models of DMD.

项目总结/文摘

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Skeletal Muscle MicroRNAs: Their Diagnostic and Therapeutic Potential in Human Muscle Diseases.

DOI：
10.3233/jnd-140058
发表时间：
2015
期刊：
Journal of neuromuscular diseases
影响因子：
3.3
作者：
Alexander MS;Kunkel LM
通讯作者：
Kunkel LM

Tandem duplication within the DMD gene in Labrador retrievers with a mild clinical phenotype.

DOI：
10.1016/j.nmd.2022.08.001
发表时间：
2022-10
期刊：
NEUROMUSCULAR DISORDERS
影响因子：
2.8
作者：
Shelton, G. Diane;Minor, Katie M.;Vieira, Natassia M.;Kunkel, Louis M.;Friedenberg, Steven G.;Cullen, Jonah N.;Guo, Ling T.;Zatz, Mayana;Mickelson, James R.
通讯作者：
Mickelson, James R.

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy.

DOI：
10.1080/21678707.2016.1240613
发表时间：
2016
期刊：
Expert opinion on orphan drugs
影响因子：
0.8
作者：
Spinazzola JM;Kunkel LM
通讯作者：
Kunkel LM

Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype.

DOI：
10.1016/j.cell.2015.10.049
发表时间：
2015-11-19
期刊：
Cell
影响因子：
64.5
作者：
Vieira NM;Elvers I;Alexander MS;Moreira YB;Eran A;Gomes JP;Marshall JL;Karlsson EK;Verjovski-Almeida S;Lindblad-Toh K;Kunkel LM;Zatz M
通讯作者：
Zatz M

Diagnostic capabilities of nanopore long-read sequencing in muscular dystrophy.