权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The Role of Cortical Projection Neurons Susceptible to Progressive Degeneration w

皮质投射神经元对进行性退化敏感的作用

基本信息

批准号：
8679491
负责人：
Asif Mirza Maroof
金额：
$ 9万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8679491
关键词：
Accounting Address Affect Age Aging Aging-Related Process Amyotrophic Lateral Sclerosis Apoptosis Astrocytes Axon Biological Body Regions Brain C9ORF72 Cell Line Cell model Cells Cerebral cortex Cessation of life Characteristics Clinical Clinical Pathology Coculture Techniques Complex Conscious Coupled Dementia Development Disease Disease Progression Disease model Elderly Electrophysiology (science)Environment Exhibits Fibroblasts Foundations Frontotemporal Lobar Degenerations Functional disorder Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals Heterogeneity Human Impairment In Vitro Individual Language Lead Light Lobe Longevity Memory Methods Microglia Molecular Molecular Profiling Morphology Motor Neurons Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurologic Neurons Onset of illness Pathology Pathway interactions Patients Perception Phase Phenotype Play Population Positioning Attribute Predisposition Process Property Prosencephalon Protocols documentation RNA-Binding Proteins Reporter Research Role Specific qualifier value Spinal Spinal Cord Staging Subgroup Symptoms Synapses Testing Thinking Toxic effect Transgenic Mice Work age related aging brain aging population base clinical phenotype environmental stressor in vivo induced pluripotent stem cell insight loss of function mind control mouse model mutant nervous system disorder neurochemistry neuron loss neurotoxicity novel progressive neurodegeneration protein aggregate public health relevance

项目摘要

DESCRIPTION (provided by applicant): Dementia is a debilitating neurological disorder resulting in the dysfunction of the cerebral cortex, the part of the brain controlling perception, memory, thoughts, language, and consciousness. Frontotemporal lobar degeneration (FTLD) is the most common cause of neurological impairment in the geriatric population, and represents a group of clinically, neuropathologically, and genetically heterogeneous disorders, with significant overlap between the neurodegenerative mechanism and the clinical phenotype. Amyotrophic lateral sclerosis (ALS) and FTLD are highly related conditions that are considered as part of a pathobiological spectrum, which begins in distinct regions of the body and propagates with age. Clinical pathology reveals the presence of aggregated protein inclusions that correspond to a loss of function in specific neuronal cell populations. To characterize how these pathobiological processes occur in the neuronal populations most susceptible to disease, I developed methods to direct the differentiation of human induced pluripotent stem (iPS) cells, derived from healthy and FTLD diseased human patient fibroblasts, into multiple cortical neuronal populations in vitro. Through a combination of hypothesis-driven and discovery-driven approaches, cortical neurons will be used to search for disease-relevant differences between healthy and ALS/FTLD patient- derived neurons. These cortical neurons will be compared in the presence or absence of environmental stressors to search for differences in survival, morphology, electrophysiology, and transcriptional profiles. Furthermore, the effect of mutations in the chromosome 9 open reading frame 72 (C9orf72), a gene implicated for its prominent role in both ALS and FTLD, will be studied from both transgenic mouse models and patient-derived human IPS cells. Taken together, these studies have the potential to identify novel environmental and genetic factors implicated in the progression of FTLD. Through the development of a human cell-based platform to model disease, coupled with known clinical and pathological symptoms, these studies would provide the foundation necessary to unravel the biological mechanisms of degeneration that occur in the aging brain.

描述（由申请人提供）：痴呆症是一种使人衰弱的神经系统疾病，导致大脑皮层功能障碍，大脑中控制感知、记忆、思想、语言和意识的部分。额颞叶退行性变（FTLD）是老年人群中最常见的神经损伤原因，代表了一组临床、神经病理学和遗传异质性疾病