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？

基本信息

批准号：
8478219
负责人：
Mark F Mehler
金额：
$ 31.13万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8478219
关键词：
Address Adult Adverse effects Affect Aging-Related Process Alzheimer&apos s Disease Behavior Behavioral Biological Markers Biological Models Biological Neural Networks Biological Process Birth Cell Death Cells Cellular Stress Response Cessation of life Characteristics Clinical Cognition Disorders Comorbidity Complex Corpus striatum structure Development Disease Disease model Early Diagnosis Elderly Event Evolution Exhibits Experimental Models Fostering Functional disorder Genes HDAC1 gene Homeostasis Huntington Disease Impairment 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 Proteins Research Risk Science Seminal Staging Stem cells United States National Institutes of Health aging brain base body system cell injury developmental disease disease phenotype genetic manipulation mouse model mutant neurodegenerative phenotype neurodevelopment neurogenesis novel pathological aging prevent programs public health relevance stressor theories therapeutic target

项目摘要

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

神经退行性疾病的发病机制仍不清楚。这些不同的衰老大脑疾病的标志是，在这些长寿的神经元亚型诞生数十年后，特定疾病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侧重于定义成年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，而不是最终常见致病过程的连续体。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的区域程序的细微损伤造成了选择性神经元和神经网络对一系列晚年的脆弱性压力源。与我们的假设一致，我们对亨廷顿病和阿尔茨海默病小鼠敲入模型中发育干细胞介导的损伤的互补特征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存在重要致病关联的可能性。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、病理和神经生理学标志的发生之间的因果关系。作为概念证明，我们将采用亨廷顿病小鼠模型，通过在发育前后消除或诱导突变基因的表达，并评估基因操作对进化的影响，来确定早期发育障碍是否直接导致该疾病。选择性细胞脆弱性、功能障碍和神经变性的特征概况。我们的假设的验证将提供令人信服的实验证据，证明亨廷顿病可能代表一类基本的新型发育障碍，对理解其他神经退行性疾病的发病机制具有直接影响。实现这一非常规假设的目标将解决生物医学中最令人烦恼的概念问题之一，这些问题阻碍了该领域早期诊断、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。该提案特别适合 EUREKA 机制，因为它在解决极其广泛的科学以及特别困难的生物医学问题方面具有概念新颖性。