Nanofibrous Scaffolds for Transplantation of Human Dopaminergic Neurons

用于人类多巴胺能神经元移植的纳米纤维支架

基本信息

批准号：
9134228
负责人：
PRABHAS V MOGHE
金额：
$ 23.25万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9134228
关键词：
3-Dimensional Address Affect Biocompatible Materials Biological Biological Neural Networks Biological Preservation Brain Cell Culture Techniques Cell Therapy Cell Transplantation Cell Transplants Cells Cellularity Central Nervous System Diseases Corpus striatum structure Cues Deep Brain Stimulation Development Disease Disease model Encapsulated Engineering Engraftment Environment Equilibrium Genetic Goals Growth Health Health Care Costs Human Hydrogels In Vitro Intervention Investigation Kinetics Methods Midbrain structure Mus Neck Nerve Degeneration Neurodegenerative Disorders Neurons Outcome Outcome Study Parkinson Disease Peptides Pharmacotherapy Recovery of Function Replacement Therapy Reporting Role Source Stem cell transplant Stem cells Substantia nigra structure Survival Rate Symptoms Tissues Transplantation Transplanted tissue Work aging population base brain tissue design dopaminergic neuron excitatory neuron genome analysis genome sequencing high risk human stem cells immunogenic implantation improved in vivo induced pluripotent stem cell innovation insight interest motor control mouse model nanofiber nerve supply neural circuit novel reduce symptoms scaffold transcription factor whole genome

项目摘要

DESCRIPTION (provided by applicant): This project aims to design innovative scaffolds that will integratively address two critical barriers for treating neurodegenerative diseases: (a) Cell Sourcing: support the maturation, specification, and function of reprogrammed human stem cell-derived neurons in vitro and (b) Subtype-specific Neuronal Transplantation: enable efficacious transplantation to treat neurodegenerative diseases in vivo. The central hypothesis is that 3D engineered microscale niches (EMNs) based on nanofibrous hydrogel scaffolds can support the induction and maturation of subtype specific neurons in vitro prior to transplantation and promote the survival and enhanced functional interaction with host tissue following transplantation. A specific application of interest to this project is the treatment of neurodegenerative diseases like Parkinson's disease (PD). To achieve our goal, two specific aims are proposed. The first aim is concerned with designing maturation-guiding EMNs of induced pluripotent stem cell (iPSC)-derived reprogrammed dopaminergic (DA) neurons. The 3-D EMNs will be based on transcription factor-transduced iPSCs cultured within nanofibrous hydrogels fabricated from self-assembling minimally immunogenic peptides. To guide the maturation and specification of the DA neurons, the EMNs will be functionalized with subtype specific cues. We will determine the emergent subpopulations of transplanted cells and examine changes in innervated host tissue through whole genome sequencing. The second aim will be focused on transplanting self-actuating EMNs of DA and excitatory neurons into the striatum of a mouse PD model. We hypothesize that a self-functioning E-DA mini neural circuitry within a microscaffold environment will provide sufficient excitatory drive to promote enhanced functional interaction of DA neurons with host tissue in vivo. We will transplant the self-actuating EMNs of E and DA neurons into the striatum of mice lacking DA innervations. We will evaluate the ability of self-actuating EMNs of E and DA neurons to improve functional deficits in the Parkinson's disease symptoms, and again examine maturation outcomes of transplanted cells and innervated host tissues. The overall outcomes from this study will help to address the critical barriers such as the functioning and survival of transplanted tissue in the field of cell-replacement therapies for neurodegenerative diseases.

描述（由申请人提供）：该项目旨在设计创新支架，综合解决治疗神经退行性疾病的两个关键障碍：（a）细胞来源：支持体外重新编程的人类干细胞衍生神经元的成熟、规范和功能(b) 亚型特异性神经元移植：使移植能够有效治疗体内神经退行性疾病。核心假设是基于 3D 工程微尺度生态位 (EMN)。纳米纤维水凝胶支架可以在移植前支持体外亚型特异性神经元的诱导和成熟，并促进移植后的存活并增强与宿主组织的功能相互作用，该项目感兴趣的一个具体应用是治疗帕金森病等神经退行性疾病。为了实现我们的目标，提出了两个具体目标，第一个目标是设计诱导多能干细胞 (iPSC) 衍生的重编程多巴胺能 (DA) 的成熟引导 EMN。 3-D EMN 将基于在由自组装最低免疫原性肽制成的纳米纤维水凝胶中培养的转录因子转导的 iPSC，为了指导 DA 神经元的成熟和规范，EMN 将通过亚型特异性线索进行功能化。我们将确定移植细胞的新兴亚群，并通过全基因组测序检查受神经支配的宿主组织的变化。第二个目标将集中于移植自驱动。我们将 DA 和兴奋性神经元的 EMN 放入小鼠 PD 模型的纹状体中，发现微支架环境中的自我功能 E-DA 微型神经回路将提供足够的兴奋性驱动，以促进 DA 神经元与体内宿主组织的功能相互作用增强。我们将E和DA神经元的自驱动EMN移植到缺乏DA神经支配的小鼠纹状体中，我们将评估E和DA神经元的自驱动EMN的能力。 DA 神经元可改善帕金森病症状的功能缺陷，并再次检查移植细胞和受神经支配的宿主组织的成熟结果，这项研究的总体结果将有助于解决关键障碍，例如移植组织的功能和存活。神经退行性疾病的细胞替代疗法。