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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：
9018254
负责人：
PRABHAS V MOGHE
金额：
$ 19.1万
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9018254
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 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 public health relevance scaffold transcription factor

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，其将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：支持体外重编程人干细胞衍生神经元的成熟、特化和功能，以及（B）亚型特异性神经元移植：使有效的移植能够在体内治疗神经退行性疾病。中心假设是基于纳米纤维水凝胶支架的3D工程化微尺度龛（EMN）可以在移植前支持亚型特异性神经元的体外诱导和成熟，并促进移植后与宿主组织的存活和增强的功能相互作用。该项目的一个具体应用是治疗神经退行性疾病，如帕金森病（PD）。为了实现我们的目标，我们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）神经元的成熟指导EMN。3-D EMN将基于在由自组装最小免疫原性肽制造的纳米纤维水凝胶内培养的转录因子转导的iPSC。为了引导DA神经元的成熟和特化，将用亚型特异性线索使EMN功能化。我们将通过全基因组测序确定移植细胞的紧急亚群并检查受神经支配的宿主组织的变化。第二个目标将集中在移植的DA和兴奋性神经元的自致动EMN到纹状体的小鼠PD模型。我们假设，一个自我功能的E-DA微型神经回路内的微支架环境将提供足够的兴奋性驱动，以促进增强功能的DA神经元与宿主组织在体内的相互作用。我们将E和DA神经元的自启动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神经元的自致EMN改善帕金森病症状中的功能缺陷的能力，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神经退行性疾病细胞替代疗法领域中移植组织的功能和存活等关键障碍。