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

• 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
• 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; 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

 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（应用程序提供）：该项目旨在设计创新的脚手架，这些脚手架将集成解决两个关键障碍，以治疗神经退行性疾病：（a）支持细胞的源：支持重编程的人类干细胞衍生的神经元在体内的成熟，规格和功能，并在体系中治疗特异性神经元启用启用效率：体内。中心假设是基于纳米纤维水凝胶支架的3D工程显微镜壁ches（EMN）可以在移植前在体外支持亚型特异性神经元的诱导和成熟，并促进生存并增强移植后与宿主组织的功能相互作用。该项目的特定兴趣应用是治疗诸如帕金森氏病（PD）之类的神经退行性疾病。为了实现我们的目标，提出了两个具体目标。第一个目的是设计诱导多能干细胞（IPSC）衍生的重编程多巴胺能（DA）神经元的成熟引导EMN。 3-D EMN将基于转录因子转移的IPSC，该IPSC在由自组装的微型免疫原性Petides制造的纳米纤维水凝胶中培养。为了指导DA神经元的成熟和规范，EMN将通过亚型特定线索功能化。我们将通过整个基因组测序来确定移植细胞的新兴亚群和神经宿主组织中的检查变化。第二个目标将集中于将DA和兴奋性神经元的自我激活EMN移植到小鼠PD模型的纹状体中。我们假设在显微镜环境中具有自我功能的E-DA Mini神经元回路将提供足够的DA神经元与体内宿主组织的激动人心的功能相互作用。我们将将E和DA神经元的自我肌肉EMN移植到缺乏DA神经的小鼠的纹状体中。我们将评估E和DA神经元的自我激活EMN改善帕金森氏病症状中功能缺陷的能力，并再次检查移植细胞和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，例如在神经退行性疾病的细胞替代疗法领域中移植组织的功能和存活。