FIBRIN BASED SCAFFOLDS FOR SPINAL CORD INJURY

用于脊髓损伤的纤维蛋白支架

• 批准号: 8260336
• 负责人: Shelly Elese Sakiyama-Elbert
• 金额: $ 32.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260336
• 关键词: Acute; Address; Adult; Age; Amyotrophic Lateral Sclerosis; Biocompatible Materials; Caring; Cell Adhesion; Cell Fraction; Cell Line; Cell Transplantation; Cells; Chondroitin ABC Lyase; Clinical; Combined Modality Therapy; Cues; Development; Drug Delivery Systems; Environment; Erinaceidae; Fiber; Fibrin; Future; Glycolates; Goals; Grant; Green Fluorescent Proteins; Growth Factor; In Vitro; Incidence; Individual; Injury; Kinetics; Knowledge; Microspheres; Modeling; Motor Neurons; Mus; Natural regeneration; Nature; Nerve Regeneration; Neuraxis; Neurites; Neurodegenerative Disorders; Neurons; Neurotrophin 3; Oligodendroglia; Pain; Patients; Peptides; Pharmaceutical Preparations; Population; Productivity; Protocols documentation; Puromycin; Quality of life; Recovery of Function; Resistance; Signal Transduction; Site; Sonic Hedgehog Pathway; Spinal Cord; Spinal Cord Lesions; Spinal cord injury; Spinal cord injury patients; Stimulus; Testing; Therapeutic; Time; Tissues; Transplantation; Tretinoin; United States; allodynia; base; cost; embryonic stem cell; improved; in vivo; prevent; progenitor; public health relevance; receptor; relating to nervous system; response; scaffold; spinal cord regeneration; transcription factor; tumor

DESCRIPTION (provided by applicant): The unifying hypothesis of this proposal is that the use of biomaterial scaffolds is critical to the development of successful therapies for spinal cord injury. In the absence of a biomaterial scaffold that can help bridge the injury site, the lack of regeneration promoting substrates in the injured spinal cord limits the efficacy of current drug delivery and cell transplantation approaches. We hypothesize that the biomaterial scaffolds can be used to direct the differentiation of embryonic stem cell-derived progenitor motor neurons (pMNs), present growth factor trophic cues and deliver drugs to overcome the inhibitory nature of the adult spinal cord. Through the use of a biomaterial scaffold we hypothesize that we will be able to present combination therapies necessary to achieve significant regeneration following spinal cord injury. This hypothesis will be tested systematically by addressing the following specific aims, all of which are necessary to achieve the goal of spinal cord regeneration. The aims of this proposal are: (1) to test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable the survival and differentiation of embryonic stem cell-derived progenitor motor neurons (pMNs) into motoneurons in an in vitro setting at levels comparable to or better than that observed with traditional differentiation protocols. (2) To test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable enhanced survival and differentiation of embryonic stem cell-derived motoneuron progenitors (pMNs) into motoneurons compared with pMN transplantation alone (no scaffold) in the in vivo setting of sub-acute (14 day) spinal cord injury. (3) To test the hypothesis that the combination of a biomaterial scaffold (with growth factor delivery), cell transplantation, and delivery of drugs to overcome the inhibitory cues of the adult spinal cord, will provide a combination therapy that is able to achieve regeneration following sub-acute (14 day) spinal cord injury. PUBLIC HEALTH RELEVANCE: Spinal cord injury is a major clinical problem. In the United States, about 12,000 people per year join the population of approximately 200,000 traumatic spinal cord injury patients. Spinal cord injuries typically occur in young patients (average age of 32, 55% of injuries occur at ages 16 to 30) and the impact of these injuries on the quality of life and productivity of these individuals is dramatic. In addition, the average cost of caring for a patient during the first year following spinal cord injury is $307,847(58). Therapeutic approaches to be developed and the mechanistic knowledge gained in this study may contribute to future clinical therapies for spinal cord injury patients. Approaches for the transplantation of motoneurons developed in this project may also be useful for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS).

描述（由申请人提供）：该提案的统一假设是，使用生物材料支架对于开发成功的脊髓损伤疗法至关重要。在没有生物材料支架的情况下可以帮助桥接受伤部位，缺乏再生促进受伤的脊髓中的底物的限制，这限制了当前药物输送和细胞移植方法的疗效。我们假设生物材料支架可用于指导胚胎干细胞衍生的祖细胞运动神经元（PMN）的分化，当前生长因子营养提示并输送药物以克服成人脊髓的抑制性质。通过使用生物材料支架，我们假设我们将能够提出脊髓损伤后必要的合并疗法，以实现重大再生。该假设将通过解决以下特定目标来系统地检验，所有这些目标对于实现脊髓再生的目标都是必要的。 该提案的目的是：（1）检验以下假设：基于纤维蛋白的生物材料支架的生长因子递送将使胚胎干细胞衍生的祖细胞衍生的祖细胞运动神经元（PMN）的生存和分化能够在与传统分化协议相当或更好的水平的体外设置中的运动神经元中的生存和分化。 （2）为了检验以下假设：与单独的PMN移植（无脚手架）相比，在亚刺激性（14日）的情况下，与单独的PMN移植相比，从基于纤维蛋白的生物材料支架递送将使胚胎干细胞衍生的运动神经元祖细胞（PMN）的生存和分化为运动神经元。 （3）为了测试以下假设：生物材料支架（随生长因子递送），细胞移植和药物的递送以克服成年脊髓的抑制性线索，将提供一种结合疗法，能够在亚急性（14天）脊髓损伤后实现再生。 公共卫生相关性：脊髓损伤是一个主要的临床问题。在美国，每年约有12,000人加入约20万名脊髓损伤患者的人口。脊髓损伤通常发生在年轻患者中（平均年龄为32岁，55％发生在16至30岁时），这些伤害对这些人的生活质量和生产力的影响是戏剧性的。此外，脊髓损伤后的第一年，患者的平均照顾成本为307,847美元（58）。要开发的治疗方法和本研究中获得的机械知识可能有助于脊髓损伤患者的未来临床疗法。在该项目中开发的运动神经元移植的方法也可能对神经退行性疾病，例如肌萎缩性侧索硬化症（ALS）。