Neurodegenerative Diseases: A New Class of Primary Developmental Disorders?

神经退行性疾病：一类新的原发性发育障碍？

• 批准号: 8117100
• 负责人: Mark F Mehler
• 金额: $ 32.54万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117100
• 关键词: Address; Adult; Adverse effects; Affect; Aging-Related Process; Alzheimer' s Disease; Animal Model; Behavior; Behavioral; Biological Markers; Biological Models; Biological Neural Networks; Biological Process; Birth; Brain Diseases; Cell Death; Cells; Cellular Stress Response; Cessation of life; Characteristics; Clinical; Cognition Disorders; Comorbidity; Complex; Corpus striatum structure; Dementia; Development; Disease; Disease model; Early Diagnosis; Elderly; Epidemic; Event; Evolution; Exhibits; Experimental Models; Fostering; Functional disorder; Genes; HDAC1 gene; Homeostasis; Huntington Disease; Impairment; Independent Living; Individual; Institutes; Knock-in Mouse; Life; Link; Mediating; Modeling; Molecular; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Pathogenesis; Pathologic; Pathway interactions; Pattern; Prevention; Process; Productivity; Proteins; Research; Risk; Science; Screening procedure; Seminal; Staging; Stem cells; Therapeutic Agents; United States National Institutes of Health; aging brain; base; body system; cell injury; cell type; combat; developmental disease; disability; disease phenotype; genetic manipulation; mouse model; mutant; neurodegenerative phenotype; neurodevelopment; neurogenesis; novel; pathological aging; prevent; programs; public health relevance; stressor; theories; therapeutic target; tool

The pathogenesis of neurodegenerative diseases remains obscure. The hallmark of these diverse disorders of the aging brain is selective cell vulnerability in disease-specific patterns many decades after the birth of these long-lived neuronal subtypes. The standard paradigm for investigating pathological brain aging and neurodegeneration has traditionally focused on defining the biological processes and pathways mediating neuronal dysfunction and death during adult life and has considered these disorders as discrete pathological entities rather than as a continuum of a final common pathogenic process. In contrast to the standard paradigm, we hypothesize that neurodegenerative diseases represent a novel class of fundamental disorders of neural development in which subtle impairments in the regional program of stem cell-mediated neurogenesis create selective neuronal and neural network vulnerabilities to a spectrum of late-life stressors. Consistent with our hypothesis, our preliminary observations of complementary profiles of developmental stem cell-mediated impairments in mouse knock-in models of Huntington's and Alzheimer's diseases support the possibility of seminal pathogenic associations between abnormalities in the birth and the death of the vulnerable neuronal subtypes. Therefore, our Specific Aim is to establish causal links between the early developmental impairments and the occurrence of the clinical, pathologic and neurophysiologic hallmarks of the late- onset neurodegenerative process in a well-characterized disease model. As a proof of concept, we will employ Huntington's disease mouse models to determine whether the early developmental impairments are directly responsible for the disease by ablating or inducing expression of the mutant gene both before and after development and assessing the consequences of the gene manipulations for evolution of the characteristic profiles of selective cell vulnerability, dysfunction and neurodegeneration. Verification of our hypothesis will provide compelling experimental evidence that Huntington's disease may represent a fundamental new class of developmental disorders with direct implications for understanding the pathogenesis of other neurodegenerative diseases. Fulfilling the objectives of this unconventional hypothesis would address one of the most vexing conceptual problems in the biomedical sciences that have prevented progress in early diagnosis, treatment and prevention within this field: what is the underlying cause of the invariant regional cellular vulnerabilities in neurodegenerative diseases. This proposal is particularly well suited to the EUREKA mechanism because of its conceptual novelty in addressing a particularly difficult biomedical problem of exceptionally broad scientific as well as public health relevance. Moreover, the unconventional focus on developmental mechanisms mediating diseases of the aging brain and associated co-morbidities affecting multiple organ systems will create important new cross-disciplinary synergies germane to the objectives of multiple NIH Institutes.

神经退行性疾病的发病机制仍不清楚。这些老化大脑的各种疾病的标志是在这些长寿神经元亚型出生后几十年，疾病特异性模式中的选择性细胞脆弱性。研究病理性脑老化和神经退行性变的标准范式传统上集中于定义在成人生活期间介导神经元功能障碍和死亡的生物过程和途径，并将这些疾病视为离散的病理实体，而不是最终共同致病过程的连续体。与标准范式相反，我们假设神经退行性疾病代表了一类新的神经发育基本疾病，其中干细胞介导的神经发生区域程序中的细微损伤产生了选择性神经元和神经网络对晚年压力源的脆弱性。与我们的假设一致，我们在亨廷顿病和阿尔茨海默病小鼠基因敲入模型中对发育干细胞介导的损伤的互补概况的初步观察支持了脆弱神经元亚型的出生和死亡异常之间的精液致病性关联的可能性。因此，我们的具体目标是在充分表征的疾病模型中建立早期发育障碍与迟发性神经退行性过程的临床、病理学和神经生理学特征发生之间的因果关系。作为概念的证明，我们将采用亨廷顿氏病小鼠模型，通过在发育前后消除或诱导突变基因的表达，并评估基因操作对选择性细胞脆弱性、功能障碍和神经退行性特征谱进化的后果，来确定早期发育障碍是否是该疾病的直接原因。验证我们的假设将提供令人信服的实验证据表明，亨廷顿病可能代表了一个基本的新一类发育障碍与直接影响了解其他神经退行性疾病的发病机制。实现这一非传统假设的目标将解决生物医学科学中最令人烦恼的概念问题之一，这些问题阻碍了该领域内早期诊断，治疗和预防的进展：神经退行性疾病中不变的区域细胞脆弱性的根本原因是什么。这一建议特别适合尤里卡机制，因为它在解决一个特别困难的生物医学问题方面具有新奇，这个问题具有特别广泛的科学和公共卫生意义。此外，非传统的重点发展机制介导的疾病的大脑老化和相关的并发症影响多个器官系统将创造重要的新的跨学科的协同作用密切相关的多个NIH研究所的目标。