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Targeting vascular endothelium for muscular dystrophy therapy

靶向血管内皮治疗肌营养不良症

基本信息

批准号：
10379330
负责人：
ATSUSHI ASAKURA
金额：
$ 16.88万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379330
关键词：
3-Dimensional Address Affinity Anatomy Angiogenic Factor Binding Blood Blood Vessels Blood capillaries Capillary Endothelial Cell Cell Count Cell Differentiation process Cell Maintenance Characteristics Chronic Complex Data Defect Development Disease Duchenne muscular dystrophy Dystrophin Endothelial Cells Endothelium Equilibrium Fibroblast Growth Factor Fibrosis Gene Expression Generations Genes Goals Growth Histologic Homeostasis Human Image Immunization Immunize Impairment Knockout Mice Lead Ligands Llama Maintenance Membrane Mesenchymal Modeling Molecular Monoclonal Antibodies Mus Muscle Muscle Contraction Muscle Fibers Muscle Weakness Muscle function Muscle satellite cell Muscular Dystrophies Mutation Myofibroblast Myopathy Natural regeneration Notch Signaling Pathway Paracrine Communication Pathogenesis Pathologic Pathology Pathway interactions Patients Phage Display Phenotype Population Process Proteins Protocols documentation Quality of life Regenerative capacity Reporter Resolution Role Serum Severities Skeletal Muscle Snails Structure Techniques Technology Therapeutic Time Tissues Translating VEGFA gene Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Endothelium Work aged angiogenesis cell growth cell type conditional knockout density functional improvement improved knockout gene mdx mouse muscle regeneration myogenesis nanobodies notch protein novel novel therapeutics postnatal prevent receptor recruit repaired satellite cell self-renewal skeletal muscle wasting stem cell population stem cells therapeutic target transcription factor

项目摘要

ABSTRACT Skeletal muscle is a highly ordered, yet complex tissue which contains several cell types that interact with each other to maintain structure and homeostasis. Muscle satellite cells (SCs) are a stem cell population responsible for muscle growth, repair and regeneration. Maintenance of the balance between SC differentiation and self- renewal is required for muscle homeostasis. A defect in self-renewal ability leads to a decrease in SC number, resulting in depletion of the SC pool and reduced muscle regeneration capacity, which occurs in aged and diseased muscle, including Duchenne muscular dystrophy (DMD). DMD is a progressive disorder in which the absence of the dystrophin protein results in loss of the dystrophin bridge at the muscle membrane. Recent work demonstrates the angiogenic impairment of the ECs in DMD model mdx mice. We demonstrates the increased vascular density can ameliorate phenotypes associated with DMD. However, the importance of angiogenesis in DMD treatment has not yet been well addressed. A recent study demonstrated that SCs are preferentially located next to capillary endothelial cells (ECs). However, the exact relationship between SCs and ECs has yet to be examined. Recently, we established an optimized tissue clearing protocol for skeletal muscle. We utilized fluorescent reporters for SCs and ECs along with tissue clearing to demonstrate the close proximity of SCs to capillaries in 3-dimentional imaging, suggesting the juxtavascular niche of SCs for stem cell maintenance. SCs express vascular endothelial cell growth factor (VEGF) and Notch receptors which is dynamically altered during the regeneration process. Therefore, we hypothesize that SCs recruit capillary ECs via VEGF to establish a juxtavascular niche for SC maintenance during homeostasis and regeneration. In this proposal, we will determine the extent to which an increased vascular niche in postnatal conditional knockout of Flt1 and by blocking Flt1 via anti-Flt1 nanobodies, created by a combination of llama-immunization and phage display technologies, in mdx mice can increase SC number, reduced pathological endothelial-to-mesenchymal transition (EndMT), and ameliorate phenotypes associated with DMD. Consequently, we will elucidate key molecules that regulate angio- myogenesis, including those involved in SC homeostasis, which is fundamental to developing therapeutic approaches to treat DMD. SCs and their juxtavascular niche are potential therapeutic targets to induce and maintain SC populations that slow the loss of skeletal muscle function with DMD.

摘要骨骼肌是一种高度有序的复杂组织，包含几种相互作用的细胞类型另一种是维持结构和体内平衡。肌肉卫星细胞（SC）是一种干细胞群，促进肌肉生长修复和再生维持SC分化和自我调节之间的平衡更新是肌肉稳态所必需的。自我更新能力的缺陷导致SC数量的减少，导致SC池的耗尽和肌肉再生能力的降低，这发生在老年人和患病肌肉，包括杜氏肌营养不良症（DMD）。DMD是一种进行性疾病，肌营养不良蛋白的缺失导致肌膜上肌营养不良蛋白桥的丧失。最近的工作证明了DMD模型mdx小鼠中EC的血管生成损伤。我们证明了增加的血管密度可以改善DMD相关的表型。然而，血管生成的重要性， DMD治疗尚未得到很好的解决。最近的一项研究表明，SC优先位于紧挨着毛细血管内皮细胞（EC）。然而，SC和EC之间的确切关系尚未得到证实。考察最近，我们建立了一个优化的骨骼肌组织清除协议。我们利用 SC和EC的荧光报告分子沿着组织清除，以证明SC与毛细血管的三维成像，表明近血管的干细胞的干细胞维护的生态位。SCS 表达血管内皮细胞生长因子（VEGF）和Notch受体，再生过程。因此，我们假设SC通过VEGF募集毛细血管内皮细胞，以建立一个新的血管内皮细胞。在稳态和再生过程中维持SC的血管旁生态位。在本提案中，我们将确定出生后条件性敲除Flt 1和通过阻断Flt 1，抗Flt 1纳米抗体，通过羊驼免疫和噬菌体展示技术的组合产生，在mdx中小鼠可以增加SC数量，减少病理性内皮-间质转化（EndMT），改善与DMD相关的表型。因此，我们将阐明调节血管生成的关键分子。肌生成，包括参与SC稳态的那些，这是开发治疗性药物的基础。治疗DMD的方法SC和它们的近血管生态位是诱导和治疗的潜在靶点，维持延缓DMD骨骼肌功能丧失的SC群体。