Notch-Modulatory Hydrogel for Dystrophic Muscle Stem Cell Rejuvenation and Expansion

用于营养不良性肌肉干细胞复兴和扩张的缺口调节水凝胶

• 批准号: 10629737
• 负责人: Woojin Han
• 金额: $ 2.98万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-01-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10629737
• 关键词: Autologous; Cell Culture Techniques; Cell Therapy; Defect; Duchenne muscular dystrophy; Dystrophin; Engineering; Failure; Generations; Genes; Genetic Diseases; Goals; Hydrogels; Life Expectancy; Mechanics; Mitogen-Activated Protein Kinases; Muscle; Muscle Cells; Muscle satellite cell; Outcomes Research; Parents; Pathway interactions; Patients; Proteins; Rejuvenation; Research; Stem cell transplant; Technology; Therapeutic; Translations; Transplantation; clinical translation; curative treatments; gene correction; muscle degeneration; notch protein; restoration; stem cell therapy; Autologous; Cell Culture Techniques; Cell Therapy; Defect; Duchenne muscular dystrophy; Dystrophin; Engineering; Failure; Generations; Genes; Genetic Diseases; Goals; Hydrogels; Life Expectancy; Mechanics; Mitogen-Activated Protein Kinases; Muscle; Muscle Cells; Muscle satellite cell; Outcomes Research; Parents; Pathway interactions; Patients; Proteins; Rejuvenation; Research; Stem cell transplant; Technology; Therapeutic; Translations; Transplantation; clinical translation; curative treatments; gene correction; muscle degeneration; notch protein; restoration; stem cell therapy

PROJECT ABSTRACT Duchenne muscular dystrophy is a genetic disease caused by defects in a protein known as dystrophin. Dystrophin functions to provide structural and mechanical stability to the muscle cells; and the absence of functional dystrophin in Duchenne muscular dystrophy leads to progressive muscle degeneration, weakness, and a significantly reduced life expectancy due to cardiorespiratory failure. There is no cure. As a potential curative therapy, restoration of dystrophin through muscle stem cell transplantation is actively being explored, but the clinical translation of these efforts is hampered by the inability to generate large quantities of muscle stem cells in dishes without compromising their therapeutic potency. In addition, it is also very challenging to expand muscle stem cells derived from dystrophic muscles in dishes due to their inherent functional deficits. This further limits strategies to gene correct patient-derived muscle stem cells outside the body, grow them in a dish, and transplant the functional muscle stem cells in an autologous manner. In this Diversity Supplement application, we will develop a Notch-modulatory muscle stem cell culture platform that enables the generation of large quantities of therapeutically potent muscle stem cells. This research strengthens and expands the scope of the parent R01 project by engineering a hydrogel platform to support dystrophic muscle cell expansion for cell therapy applications. Towards this goal, Aim 1 will engineer a Notch-modulatory hydrogel for rejuvenating dystrophic muscle stem cells ex vivo. Aim 2 will determine the effects of suppressing p38α/β mitogen-activated protein kinase (MAPK) activity of dystrophic muscle stem cells maintained within the Notch-modulatory hydrogel long-term. The outcomes of this research will trailblaze a pathway towards personalized (autologous) muscle stem cell therapy for safely treating Duchenne muscular dystrophy, where such technologies will also enable ex vivo gene correction on the muscle stem cells outside the patient's body before being re-introduced to restore dystrophin.

项目摘要 Duchenne肌肉营养不良是由称为肌营养不良蛋白的蛋白质缺陷引起的遗传疾病。 肌营养不良蛋白的功能可为肌肉细胞提供结构和机械稳定性。还有 Duchenne肌肉营养不良中的功能性肌营养不良蛋白会导致肌肉变性，无力， 以及由于心肺衰竭而导致的预期寿命大大降低。无法治愈。作为潜力 治疗疗法，通过肌肉干细胞移植恢复肌营养不良蛋白正在积极探索， 但是，由于无法产生大量肌肉茎，这些努力的临床翻译受到了阻碍 菜肴中的细胞而不会损害其治疗效力。此外，扩展也非常挑战 肌肉干细胞由于遗传功能性缺乏而源自营养不良的肌肉。进一步 限制策略以纠正体内患者衍生的肌肉干细胞，在盘子中种植，然后 以自体方式移植功能性肌肉干细胞。在这种多样性补充应用中， 我们将开发一个凹口调节的肌肉干细胞培养平台，使大型产生 量的治疗潜在肌肉干细胞。这项研究能够增强并扩大 父R01通过工程化水凝胶平台来支持细胞营养不良的肌肉细胞扩展 治疗应用。为了实现这一目标，AIM 1将设计一个凹槽调节水凝胶以恢复活力 营养不良的肌肉细胞离体。 AIM 2将确定抑制P38α/β有丝分裂原激活的影响 蛋白激酶（MAPK）的营养不良肌肉细胞的活性保持在凹槽调节水凝胶中 长期。这项研究的结果将开拓通往个性化（自体）肌肉的途径 用于安全治疗Duchenne肌肉营养不良的干细胞疗法，此类技术也将使Ex启用 在重新引入患者体内的肌肉干细胞上的体内基因校正 肌营养不良。