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

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 杜氏肌营养不良症是一种由肌营养不良蛋白缺陷引起的遗传性疾病。 肌营养不良蛋白的作用是为肌肉细胞提供结构和机械稳定性； 杜氏肌营养不良症中的功能性肌营养不良蛋白会导致进行性肌肉退化、无力、 由于心肺衰竭，预期寿命显着缩短，目前尚无法治愈。 治疗性疗法，通过肌肉干细胞移植恢复肌营养不良蛋白，正在积极探索， 但这些努力的临床转化因无法产生大量肌肉干而受到阻碍 在培养皿中培养细胞而不影响其治疗效力此外，扩增也非常具有挑战性。 由于其固有的功能缺陷，源自培养皿中营养不良的肌肉的肌肉干细胞。 限制在体外对患者来源的肌肉干细胞进行基因校正、在培养皿中培养它们的策略，以及 以自体方式移植功能性肌肉干细胞在这个多样性补充应用中， 我们将开发一个Notch调节肌肉干细胞培养平台，能够产生大量 这项研究加强并扩大了具有治疗作用的肌肉干细胞的范围。 父 R01 项目通过设计水凝胶平台来支持营养不良的肌肉细胞扩增 为了实现这一目标，Aim 1 将设计一种用于恢复活力的 Notch 调节水凝胶。 目标 2 将确定抑制 p38α/β 丝裂原激活的效果。 Notch调节水凝胶内维持营养不良性肌肉干细胞的蛋白激酶（MAPK）活性 从长远来看，这项研究的结果将为个性化（自体）肌肉开辟一条道路。 干细胞疗法可安全治疗杜氏肌营养不良症，此类技术也将使前 对患者体外的肌肉干细胞进行体内基因校正，然后重新引入以恢复 肌营养不良蛋白。