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Correction of Hurler syndrome by multipotent stem cells

多能干细胞纠正Hurler综合征

基本信息

批准号：
7154741
负责人：
Pankaj GUPTA
金额：
$ 27.63万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7154741
关键词：
Acids Adult Affect Affinity Allogeneic Bone Marrow Transplantation Animals Aspirate substance Atrophic Autologous Behavior Behavioral Binding Biochemical Biological Blood Bone Marrow Bone Marrow Transplantation Brain Brain region Brain-Derived Neurotrophic Factor Carboxy-Lyases Cause of Death Cell Adhesion Molecules Cell Proliferation Cell Size Cell Survival Cell Therapy Cells Cerebellum Cerebral cortex Cerebrospinal Fluid Characteristics Child Chondroitin Sulfates Clinical Clinical Data Cytokine Signaling Data Dermatan Sulfate Deterioration Development Disease Dopa EGF gene Electrophoresis Embryo Engraftment Ensure Enzymes Epidermal Growth Factor Erinaceidae Ethical Issues Extracellular Matrix Extracellular Matrix Proteins Failure Fetal Tissues Fibroblast Growth Factor Fibroblast Growth Factor 2 Fibroblast Growth Factor Receptors Fibronectins Functional disorder Funding GDNF gene Gangliosides Gene Delivery Gene Expression Genes Glial Fibrillary Acidic Protein Glucosylceramides Glycosaminoglycans Glypican Goals Grant Growth Growth Factor Heparan Sulfate Biosynthesis Heparan Sulfate Proteoglycan Heparitin Sulfate Hepatocyte Growth Factor Human Immunophenotyping Impairment Implant In Vitro Inborn Errors of Metabolism Individual Infiltration Inflammation Inflammatory Inherited Injury Intelligence Interferons Keratan Sulfate Knock-out L-Iduronidase Lead Life Location Mental Retardation Mesenchymal Stem Cells Metabolic Microglia Modeling Morphology Mucopolysaccharidoses Mucopolysaccharidosis I Mucopolysaccharidosis I H Mucopolysaccharidosis III Mucopolysaccharidosis VI Mucopolysaccharidosis VII Multipotent Stem Cells Mus Myelin Basic Proteins NCAM1 gene Nature Neonatal Nerve Growth Factor 1 Nerve Growth Factor Pathway Nerve Growth Factors Neuraxis Neurodegenerative Disorders Neuroglia Neurologic Neurologic Dysfunctions Neuron-Specific Enolase Neuronal Differentiation Neurons Numbers Oligosaccharides Patients Pattern Personal Satisfaction Platelet Factor 4 Platelet-Derived Growth Factor Play Proliferating Proteins Proteoglycan Psyche structure Risk Rodent Rodent Model Role SCID Mice Sampling Secondary to Serum Severities Signal Transduction Signaling Molecule Site Somatomedins Source Specificity Stem cell transplant Stem cells Stromal Cells Structure Study models Surface Plasmon Resonance Teratoma Testing Therapeutic Tissues Transforming Growth Factors Transplantation Tryptophan 5-monooxygenase Tubulin Tyrosine 3-Monooxygenase Vascular Endothelial Growth Factors Ventricular Zalcitabine adult stem cell axonal guidance base bone morphogenic protein brain tissue cell growth cell type cytokine embryonic stem cell enzyme activity enzyme deficiency enzyme pathway extracellular fetal gamma-Aminobutyric Acid gene correction graft vs host disease human embryonic stem cell human stem cells implantation improved in vivo lateral ventricle macrophage migration morphogens nerve stem cell nervous system disorder neurofilament neurogenesis neuropathology neuropsychological neurotrophic factor novel strategies novel therapeutics polysulfated glycosaminoglycan pre-clinical proteoglycan core protein reconstitution relating to nervous system senescence stem sulfation sulfotransferase synaptogenesis therapeutic gene three dimensional structure tumor

项目摘要

DESCRIPTION (provided by applicant): Novel approaches based on pathophysiologic mechanisms are needed to treat progressive neurological dysfunction and mental retardation in Hurler syndrome (MPS I). Our group has identified a multipotent adult progenitor cell (MAPC) in human and rodent bone marrow (BM), which differentiates in vitro and in vivo into all three embryonic lineages, including neuronal and glial cells (Blood 98:2615, 2001; Nature 418:41, 2002). MAPC implanted into adult rodent brains engraft, acquire neuronal and glial markers and ameliorate ischemic neurological dysfunction. MAPC may be ideal for neural tissue reconstitution/gene delivery, as they 1) are obtained from a small BM sample and proliferate without senescence 2) are efficiently transduced and express genes without losing stem cell potential 3) are free from ethical issues of embryonic/fetal tissues. During an R03 grant, we found that 1) structurally abnormal heparan sulfates (HS) in Hurler MAPC have defective binding interactions with FGF-2, thus impairing its biological activity on MAPC survival, proliferation and neural differentiation 2) normal MAPC provide trophic and corrective signals to Hurler MAPC 3) gene expression of proteoglycans (PGs), glycosaminoglycan (GAG) metabolic enzymes, cytokines and morphogens is altered in Hurler MAPC. Separately, our group found severe neuropathological and behavioral abnormalities in a murine knockout model of MPS I. We hypothesize that 1) the structural and functional abnormalities of HS contribute to the neuronal pathophysiology of Hurler syndrome by perturbing the biological activity of critical cytokines and by secondarily modulating gene expression, and 2) following intra-ventricular transplantation, normal human MAPC will engraft in the brain of neonatal immunodeficient (NOD-SCID)-MPS I mice and ameliorate behavioral abnormalities. Specific Aim (SA) 1: Compare the structure and function of HS from normal and Hurler MAPC and murine brain tissue. SA2: Test the secondary effects of accumulated GAGs and oligosaccharides on HS biosynthesis and gene expression in Hurler MAPC. SA3: Examine if the neuropathology and behavioral dysfunction in NOD-SCID-MPS I mice can be corrected by intracerebroventricular transplantation of normal human MAPC. If MAPC transplantation is of benefit in the Hurler model, similar strategies may be developed for treating diverse neurodegenerative disorders.

描述（由申请人提供）：需要基于病理生理机制的新方法来治疗Hurler综合征（MPS I）的进行性神经功能障碍和智力低下。我们的研究小组已经在人类和啮齿动物骨髓（BM）中发现了一种多能成体祖细胞（MAPC），它在体外和体内分化为所有三种胚胎谱系，包括神经元和神经胶质细胞（Blood 98: 2615,2001; Nature 418:41, 2002）。MAPC植入成年鼠脑，获得神经元和神经胶质标记物，改善缺血性神经功能障碍。MAPC可能是神经组织重建/基因传递的理想选择，因为它们1)从小的骨髓样本中获得，增殖而不会衰老2)有效地转导和表达基因而不会失去干细胞潜力3)不受胚胎/胎儿组织的伦理问题的影响。在R03资助中，我们发现1)Hurler MAPC中结构异常的硫酸肝素（HS）与FGF-2的结合相互作用存在缺陷，从而损害了其对MAPC存活、增殖和神经分化的生物活性；2)正常的MAPC为Hurler MAPC提供营养和纠正信号；3)Hurler MAPC中蛋白聚糖（pg）、糖胺聚糖（GAG）代谢酶、细胞因子和形态因子的基因表达发生改变。另外，我们小组在小鼠MPS敲除模型中发现了严重的神经病理和行为异常。我们假设1)HS的结构和功能异常通过干扰关键细胞因子的生物活性和继发调节基因表达来促进Hurler综合征的神经元病理生理，2)心室内移植后，正常人MAPC将植入新生儿免疫缺陷(NOD-SCID)-MPS I小鼠的大脑，并改善行为异常。特异性目的（SA） 1：比较正常、Hurler MAPC和小鼠脑组织HS的结构和功能。SA2：检测累积的GAGs和寡糖对Hurler MAPC中HS生物合成和基因表达的次生影响。SA3：观察正常人MAPC脑室内移植是否能纠正NOD-SCID-MPSⅰ型小鼠的神经病理和行为功能障碍。如果MAPC移植在Hurler模型中是有益的，那么类似的策略可能被开发用于治疗各种神经退行性疾病。