Molecular Genetics of Inherited Neurological Diseases

遗传性神经疾病的分子遗传学

• 批准号: 8271389
• 负责人: XANDRA OWENS BREAKEFIELD
• 金额: $ 131.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2013-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271389
• 关键词: Actins; Angiolipoma; Angiomyolipoma; Animals; Antibodies; Apoptosis; Astrocytes; Autistic Disorder; Basic Science; Biochemistry; Bioluminescence; Brain; Cell physiology; Cells; Cellular biology; Chromosome Mapping; Chromosomes; Clinical; Clinical Medicine; Clinical Trials; Clinical assessments; Collection; Complementary DNA; Complex; Control Locus; Cytoskeleton; DNA; Databases; Dendritic Spines; Dependovirus; Development; Diagnosis; Differentiation and Growth; Disease; Disease model; Doctor of Medicine; Doctor of Philosophy; Ensure; Etiology; Evaluation; Event; Family; Functional disorder; Funding; Gene Delivery; Gene Proteins; Gene Transfer; Generations; Genes; Genetic; Genomics; Genotype; Goals; Growth; Growth and Development function; HSV vector; Human; Human Genome; Image; Image Analysis; Immunology; Inherited; Injection of therapeutic agent; Institution; Interneurons; Investigational Therapies; Knock-out; Knockout Mice; Knowledge; LacZ Genes; Lesion; Life; Longevity; Maintenance; Mediating; Mental Retardation; Messenger RNA; Methods; MicroRNAs; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Genetics; Monitor; Mus; Mutation; NF1 gene; NF2 gene; Nervous System Physiology; Nervous system structure; Neurilemmoma; Neurocutaneous Syndromes; Neurofibromatosis 2; Neurofibromin 2; Neuroglia; Neurologic; Neurologic Deficit; Neurons; Neurosciences; Neurotransmitter Receptor; Null Lymphocytes; Other Genetics; Pain; Paralysed; Pathogenesis; Pathologic; Pathway interactions; Patient Care; Patients; Peripheral Nerve Schwannoma; Pharmaceutical Preparations; Phenotype; Physiological; Property; Proteins; RNA Interference; Radial; Recruitment Activity; Regulation; Research Personnel; Resolution; Robin bird; Role; Sampling; Schwann Cells; Schwannomatosis; Seizures; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Simplexvirus; Sinus; Sirolimus; Staging; Stem cells; Synapsins; Syndrome; TSC1 gene; TSC1/2 gene; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissue Banks; Tissue Sample; Tissues; Transgenic Mice; Transgenic Organisms; Translations; Tuberous Sclerosis; Tumor Bank; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; Tumor Volume; Vestibular Nerve; Viral Vector; Work; adeno-associated viral vector; cell growth; cell type; comparative genomic hybridization; database of Genotypes and Phenotypes; deafness; fibroma; gene discovery; gene function; gene replacement; gene therapy; genetic analysis; genetic pedigree; human FRAP1 protein; human TSC1 protein; human TSC2 protein; human tissue; insight; loss of function; malformation; meningioma; mouse model; neoplastic cell; nerve injury; nervous system disorder; nestin protein; neurodevelopment; neurogenetics; neuropathology; offspring; oncolytic vector; positional cloning; postnatal; pre-clinical; prenatal; programs; promoter; protein function; receptor; response; success; therapeutic evaluation; therapy development; tumor; tumor progression; vector; Actins; Angiolipoma; Angiomyolipoma; Animals; Antibodies; Apoptosis; Astrocytes; Autistic Disorder; Basic Science; Biochemistry; Bioluminescence; Brain; Cell physiology; Cells; Cellular biology; Chromosome Mapping; Chromosomes; Clinical; Clinical Medicine; Clinical Trials; Clinical assessments; Collection; Complementary DNA; Complex; Control Locus; Cytoskeleton; DNA; Databases; Dendritic Spines; Dependovirus; Development; Diagnosis; Differentiation and Growth; Disease; Disease model; Doctor of Medicine; Doctor of Philosophy; Ensure; Etiology; Evaluation; Event; Family; Functional disorder; Funding; Gene Delivery; Gene Proteins; Gene Transfer; Generations; Genes; Genetic; Genomics; Genotype; Goals; Growth; Growth and Development function; HSV vector; Human; Human Genome; Image; Image Analysis; Immunology; Inherited; Injection of therapeutic agent; Institution; Interneurons; Investigational Therapies; Knock-out; Knockout Mice; Knowledge; LacZ Genes; Lesion; Life; Longevity; Maintenance; Mediating; Mental Retardation; Messenger RNA; Methods; MicroRNAs; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Genetics; Monitor; Mus; Mutation; NF1 gene; NF2 gene; Nervous System Physiology; Nervous system structure; Neurilemmoma; Neurocutaneous Syndromes; Neurofibromatosis 2; Neurofibromin 2; Neuroglia; Neurologic; Neurologic Deficit; Neurons; Neurosciences; Neurotransmitter Receptor; Null Lymphocytes; Other Genetics; Pain; Paralysed; Pathogenesis; Pathologic; Pathway interactions; Patient Care; Patients; Peripheral Nerve Schwannoma; Pharmaceutical Preparations; Phenotype; Physiological; Property; Proteins; RNA Interference; Radial; Recruitment Activity; Regulation; Research Personnel; Resolution; Robin bird; Role; Sampling; Schwann Cells; Schwannomatosis; Seizures; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Simplexvirus; Sinus; Sirolimus; Staging; Stem cells; Synapsins; Syndrome; TSC1 gene; TSC1/2 gene; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissue Banks; Tissue Sample; Tissues; Transgenic Mice; Transgenic Organisms; Translations; Tuberous Sclerosis; Tumor Bank; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; Tumor Volume; Vestibular Nerve; Viral Vector; Work; adeno-associated viral vector; cell growth; cell type; comparative genomic hybridization; database of Genotypes and Phenotypes; deafness; fibroma; gene discovery; gene function; gene replacement; gene therapy; genetic analysis; genetic pedigree; human FRAP1 protein; human TSC1 protein; human TSC2 protein; human tissue; insight; loss of function; malformation; meningioma; mouse model; neoplastic cell; nerve injury; nervous system disorder; nestin protein; neurodevelopment; neurogenetics; neuropathology; offspring; oncolytic vector; positional cloning; postnatal; pre-clinical; prenatal; programs; promoter; protein function; receptor; response; success; therapeutic evaluation; therapy development; tumor; tumor progression; vector

The goals of this Neurogenetics Center are to understand the molecular/cellular etiology and to ameliorate the course of the hereditary phakomatoses, neurofibromatosis type 2 (NF2), tuberous sclerosis (TSC) and related disorders. NF2 schwannomas can cause deafness, pain and paralysis, and meningiomas result in brain compression and occlusion of major sinuses, which are life threatening. TSC has severe manifestations including seizures, mental retardation and autism. These neurofunctional diseases share features of disrupted signaling pathways leading to abnormal neural cell development and growth due to loss of function of tumor suppressor genes. The focus of the proposed studies is on understanding genetic and cellular factors contributing to formation and progression of tumors, as well as disruption of neural development, and on generating mouse models which will allow assessment of therapeutic strategies. Project 1 (Gusella/Ramesh) - Molecular genetics of meningioma and NF-related disorders: identify additional genes and signaling pathways involved in initiation and progression of meningioma, schwannoma and related tumors, including schwannomas in schwannomatosis, and angiomyolipomas and subungual fibromas in TSC, and the role of associated proteins in cytoskeletal dynamics and abnormalities in target cells; Project 2 (Kwiatkowski) - Mouse brain models of tuberous sclerosis: create and analyze authentic brain models of TSC in conditional Tsc1 knock-out mice to gain a detailed understanding of developmental events contributing to these lesions, including role of neuroprecursor cells and response to rapamycin therapy. Project 3 (Breakefield/Sena-Esteves) - Vector query and therapy for NF2 and TSC lesions: use viral vectors to evaluate the contribution of different Tsc1-null cell types to abnormal development of the brain and to rescue a Tsc1-null neurologic phenotype by gene replacement. MicroRNA profiling of meningioma will be used to elucidate changes in concert with genomic and mRNA analyses in Project 1. Mouse models of schwannomas will be used to investigate ontogeny and treatment. These projects will be supported by Cores for Administration (Breakefield), Clinical co-ordination (Thiele/Plotkin) including clinical assessment, databases and genotype/phenotype correlations and Neuropathology and tumor banking (Stemmer-Rachamimov/Louis) ensuring reliable collection and neuropathologic assessment of human and mouse tumor/tissue samples. These cores provide a major strength to the Center in coordinating basic research and clinical investigation to facilitate translation to patient care. Collectively these studies provide a concerted effort toward understanding the genes, proteins and cells that contribute to associated tumors and malformations in the nervous system underlying neurologic deficits in NF2 and TSC for the purposes of more effective diagnosis and development of treatment paradigms.

这个神经遗传学中心的目标是了解分子/细胞病因，并改善遗传性恐惧症，神经纤维瘤病2（NF2），结核性硬化症（TSC）和相关疾病。 NF2 schwannomas会导致耳聋，疼痛和麻痹，脑膜瘤导致 大脑压缩和主要鼻窦的阻塞，这是威胁生命的。 TSC具有严重的表现，包括癫痫发作，智力低下和自闭症。这些神经功能疾病具有破坏的信号通路的特征，导致由于肿瘤抑制基因功能的丧失而导致神经细胞异常的发育和生长。拟议的研究的重点是理解造成肿瘤形成和进展的遗传和细胞因素，以及神经的破坏 开发以及生成小鼠模型，以评估治疗策略。 项目1（Gusella/ramesh） - 脑膜瘤和NF相关疾病的分子遗传学：确定与脑膜瘤，schwannoma及其相关肿瘤的起始和进展有关的其他基因和信号传导途径，包括schwannomatisois和Angiomyolipomas和subengual纤维中的Schwannomas，以及TSC中的蛋白质和蛋白质纤维素中的cy蛋白，并具有相关的蛋白质蛋白质，并具有相关的蛋白质，并具有相关的蛋白质。目标异常 细胞；项目2（Kwiatkowski） - 结节性硬化症的小鼠大脑模型：在条件TSC1敲除小鼠中创建和分析TSC的真实大脑模型，以详细了解有助于这些病变的发育事件，包括神经蛋白酶细胞的作用以及对Rapamycin疗法的反应。项目3（Breakefield/Sena-Esteves） - NF2和TSC病变的矢量查询和治疗：使用病毒矢量评估不同TSC1无效细胞类型对大脑异常发育的贡献，并通过基因替换来营救TSC1-NULL神经学表型。脑膜瘤的microRNA分析将用于阐明项目1中的基因组和mRNA分析的变化。小鼠造型小鼠模型将用于研究个体发育和治疗。这些项目将得到核心核心（Breakefield），临床协调性（Thiele/Plotkin）的支持，包括临床评估，数据库以及基因型/表型相关性以及神经病理学和肿瘤银行（STEMMER-RACHAMIMOV/LOUIS），以确保可靠的收集和神经病理学评估人类和人类和小鼠tumor/Else鼠标/组织tumaper。这些核心为中心提供了协调基础研究和临床研究的主要优势，以促进转化为 病人护理。这些研究共同为理解NF2和TSC中神经系统缺陷的神经系统中相关肿瘤和畸形的基因，蛋白质和细胞提供了一致的努力，以进行更有效的诊断和发展治疗范式。