Guinea pigs as a model of in utero stem cell therapy for spina bifida

豚鼠作为子宫内干细胞治疗脊柱裂的模型

基本信息

批准号：
9299355
负责人：
Aijun Wang
金额：
$ 7.85万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9299355
关键词：
Anatomy Animal Model Animals Birth Bladder Caring Categories Cavia Chemicals Child Childhood Cognitive Communities Congenital Abnormality Cranial Nerves Data Defect Deformity Development Disease Effectiveness Extracellular Matrix Fetal Therapies Fetus Gestational Age Histologic Histology Human Hysterotomy Incontinence Intervention Intestines Laparotomy Lesion Manuals Mechanics Medical Meningomyelocele Mesenchymal Stem Cells Methods Modeling Morbidity - disease rate Musculoskeletal Natural History Neural Tube Closure Neural tube Operative Surgical Procedures Oryctolagus cuniculus Paralysed Physical Rehabilitation Positioning Attribute Pregnancy Protocols documentation Rattus Recovery of Function Reproducibility Research Research Personnel Sheep Spinal Spinal Cord Spinal Dysraphism Stem cells Surgeon Surgical sutures Techniques Time Trauma Tretinoin United States Veterinarians arm base cognitive disability cognitive rehabilitation cost cost effective disability experimental study falls feeding fetal hindbrain improved in utero independent ambulation novel therapeutics outcome forecast pregnant pup repaired stem cell therapy success

项目摘要

Abstract Spina bifida (SB) is the most common cause of lifelong childhood paralysis in the United States. SB results from the incomplete closure of the neural tube during the fourth week of gestation. The exposed spinal cord sustains intrauterine chemical and mechanical trauma, leaving children with lifelong paralysis, bowel and bladder incontinence, musculoskeletal deformities, and cognitive disabilities. These disabilities require extensive medical care and ongoing physical and cognitive rehabilitation, making SB one of the most costly childhood diseases. Recent studies – including our own – have suggested that fetal interventions with stem cells or other techniques have the potential to improve the prognosis of children born with this devastating disease. While the medical and scientific community has never been better positioned to develop new groundbreaking therapies for SB, the field suffers from a lack of suitable animal models. To accurately model SB, animals must have a long gestation, tolerate surgical manipulation of the fetus, and be sufficiently developed at birth to allow for the assessment of locomotor function. Commonly used animal models of SB include rats, rabbits, and sheep. To date, small animal models have been largely unsuitable for the development of new therapies; due to their small size and short gestation surgical manipulation of the fetus cannot be performed at an early enough gestational age to accurately model human SB. Furthermore, functional locomotor data cannot be collected from these models as neither rats nor rabbits are ambulatory at birth. While large animal models have longer gestational times, are more suited for fetal manipulation, and are ambulatory shortly after birth, they are prohibitively expensive and labor intensive. To statistically power a single arm of a sheep study will cost well over $100,000 and can take a team of surgeons and veterinarians an entire year to complete. We propose to develop a high-throughput, cost effective small animal model of SB using guinea pigs. Guinea pigs have a natural history that makes the species uniquely suited for SB in utero treatment research. Guinea pigs have the longest gestation of any commonly used small animal models, three times as long as rats and twice as long as rabbits. Additionally, guinea pigs represent the only commonly used small animal model capable of ambulation and independent feeding at birth. We propose to use guinea pigs to develop a reproducible small animal model of SB that will allow investigators to quickly and economically assess the effectiveness of new in utero therapies.

抽象的脊柱裂 (SB) 是美国儿童终生瘫痪的最常见原因 SB 是由于神经管在第四周内不完全闭合造成的。暴露的脊髓承受宫内化学和机械创伤，儿童终生瘫痪、肠和膀胱失禁、肌肉骨骼疾病这些残疾需要广泛的医疗护理和治疗。持续的身体和认知康复，使 SB 成为成本最高的童年之一最近的研究（包括我们自己的研究）表明，胎儿干预与疾病有关。干细胞或其他技术有可能改善患有先天性遗传病的儿童的预后而医学界和科学界却从未如此好过。该领域旨在为 SB 开发新的突破性疗法，但缺乏合适的动物模型要准确地模拟SB，动物必须有较长的妊娠期、耐受性。对胎儿进行手术操作，并在出生时充分发育以允许常用的 SB 动物模型包括大鼠、兔、迄今为止，小动物模型基本上不适合开发。新疗法；由于胎儿体积小且妊娠期短无法在足够早的胎龄下进行以准确模拟人类 SB。此外，无法从这些模型中收集功能性运动数据，因为大鼠兔子出生时也不能行走，而大型动物模型的妊娠时间较长，更适合胎儿操作，并且出生后不久即可走动，管理一只羊的一只手臂的研究成本高昂且劳动强度大。花费远超过 100,000 美元，需要外科医生和兽医团队花费一整年的时间才能完成完全的。我们建议开发一种高通量、具有成本效益的 SB 小动物模型豚鼠的自然历史使得该物种特别适合 SB。子宫治疗研究中，豚鼠的妊娠期是所有常用小型猪中最长的。动物模型的长度是老鼠的三倍，兔子的两倍。猪是唯一常用的能够行走和行走的小动物模型我们建议使用豚鼠来培养可繁殖的小型豚鼠。 SB 动物模型将使研究人员能够快速、经济地评估新子宫内疗法的有效性。