Stem cell-based biomaterials for spinal regeneration in neural tube defects

基于干细胞的生物材料用于神经管缺陷的脊柱再生

基本信息

批准号：
10000197
负责人：
Shaun Michael Kunisaki
金额：
$ 33.08万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000197
关键词：
Address Advanced Development Amniotic Fluid Animal Model Autologous Biocompatible Materials Bladder Cells Child Chronic Clinical Coculture Techniques Congenital Abnormality Data Defect Development Diagnosis Disease Embryonic Development Engineering Engraftment Ethics Functional disorder Gene Delivery Generations Glycolic-Lactic Acid Polyester Goals Human Hydrocephalus Immune Impaired cognition Implant In Vitro Injury Intervention Intestines Laboratories Leg Life Lower Extremity Mediating Meningomyelocele Modeling Morbidity - disease rate Natural regeneration Nerve Regeneration Nervous System Physiology Neural Tube Defects Neural tube Neurologic Neurons Neurosurgeon Neurotrophin 3 Oligodendroglia Operative Surgical Procedures Orthopedics Outcome Paralysed Patients Perinatal Population Pregnancy Pregnant Women Premature Labor Prenatal Diagnosis Procedures Process Property Publishing Rattus Regenerative Medicine Research Personnel Rodent Rodent Model SHH gene Safety Scientist Secondary to Sensorimotor functions Sheep Slice Source Spinal Spinal Cord Spinal Cord Diseases Spinal Dysraphism Spinal cord damage Spinal cord injury Stem cell transplant Surgeon Surgical Models System Technology Testing Time Tissues Transgenes Transplantation Tretinoin United States Viral Vector Walking Work axon regeneration base clinical translation clinically relevant combinatorial disability embryo surgery experience fetal improved in utero in vivo induced pluripotent stem cell innovative technologies insight materials science migration motor function improvement multidisciplinary myelination nerve stem cell novel operation outcome forecast overexpression paracrine postnatal pre-clinical preclinical trial prototype randomized trial recruit regenerative relating to nervous system repaired scaffold spinal cord regeneration stem cells treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Children with a severe form of spina bifida, known as myelomeningocele (MMC), suffer from substantial and life-long morbidities secondary to lower limb weakness and paralysis, hydrocephalus, cognitive impairment, bladder and bowel dysfunction, and orthopedic abnormalities. Although a randomized trial has shown a reduction of postnatal hydrocephalus after prenatal surgery, there remains a critical need to provide these children with an operative treatment that can better enhance neurologic function. Given the known regenerative properties of neural progenitor cells transplanted in other models of spinal cord injury, the application of neurons reprogrammed from amniotic fluid cells to treat MMC defects offers a novel, clinically relevant, and potentially autologous alternative to conventional fetal MMC repair. Our central hypothesis is that fetal neurosurgical treatment of spina bifida defects using a composite, cell-based neural patch with trophic factor (sonic hedgehog, neurotrophin-3) functionality can maximally enhance neuronal regeneration within the MMC spinal cord through engraftment and paracrine effects. In Specific Aim 1, we will investigate the short- term paracrine effects of neural patches on the fetal MMC spinal cord. In Specific Aim 2, we will determine the extent to which neural patches augment long-term MMC spinal cord regeneration and neurologic function in vivo. The cornerstone of this proposal is the multidisciplinary team composed of an early-stage, fetal surgeon- scientist (Dr. Kunisaki), academic neurosurgeon (Dr. Patil), senior developmental neurobiologist (Dr. O'Shea), and senior materials science engineer (Dr. Shea). The expected outcomes will have validated a regenerative medicine approach with high potential for clinical translation in the treatment of spina bifida and other spinal cord injuries.

项目概要/摘要患有严重脊柱裂（称为脊髓脊膜膨出 (MMC)）的儿童会遭受严重的继发于下肢无力和瘫痪、脑积水、认知障碍、膀胱和肠道功能障碍以及骨科异常。尽管一项随机试验表明产前手术后减少产后脑积水，仍然迫切需要提供这些对患儿进行手术治疗，可以更好地增强神经功能。鉴于已知移植到其他脊髓损伤模型中的神经祖细胞的再生特性应用羊水细胞重编程的神经元来治疗 MMC 缺陷提供了一种新颖的临床方法传统胎儿 MMC 修复的相关且潜在的自体替代方案。我们的中心假设是使用具有营养性的复合细胞神经补片对脊柱裂缺陷进行胎儿神经外科治疗因子（音刺猬、神经营养素-3）功能可以最大程度地增强神经元内的再生 MMC 脊髓通过植入和旁分泌作用。在具体目标 1 中，我们将调查短期神经斑块对胎儿 MMC 脊髓的足月旁分泌作用。在具体目标 2 中，我们将确定神经贴片在多大程度上增强长期 MMC 脊髓再生和神经功能体内。该提案的基石是由早期胎儿外科医生组成的多学科团队—— 科学家（国崎博士）、学术神经外科医生（帕蒂尔博士）、高级发育神经生物学家（奥谢博士）、和高级材料科学工程师（Shea 博士）。预期结果将验证再生在治疗脊柱裂和其他脊柱疾病方面具有高度临床转化潜力的医学方法脊髓损伤。