Role of Microglia somatic variants in Neurodegenerative diseases

小胶质细胞体细胞变异在神经退行性疾病中的作用

• 批准号: 9789572
• 负责人: Frederic Geissmann
• 金额: $ 100.39万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789572
• 关键词: Address; Adult; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Anatomy; Architecture; Award; Brain; Cancer Biology; Cell Nucleus; Cell physiology; Cells; Chronic; Clinical; Clonal Evolution; Clonality; DNA Sequence Alteration; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Environmental Risk Factor; Epidemiologic Factors; Epigenetic Process; Erythro; Etiology; Event; Frequencies; Functional disorder; Future; Gene Mutation; Genes; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic study; Genome; Genomics; Heterogeneity; Histiocytosis; Human; In Vitro; Incidence; Inherited; Laboratories; Longevity; Malignant Neoplasms; Methodology; Microglia; Modeling; Molecular; Molecular Analysis; Molecular Diagnosis; Mosaicism; Multiple Sclerosis; Mus; Mutation; Myelogenous; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Online Mendelian Inheritance In Man; Organogenesis; Parkinson Disease; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Process; Proliferating; Protocols documentation; Public Health; Publishing; Rare Diseases; Recurrence; Research; Role; Sampling; Site; Somatic Mutation; Specificity; Susceptibility Gene; Synapses; Technology; Therapeutic; Tissues; Traumatic Brain Injury; United States National Institutes of Health; Variant; Work; actionable mutation; anticancer research; astrogliosis; base; brain cell; brain tissue; developmental disease; disability; effective therapy; experimental study; gain of function; gastrulation; in vivo; innovation; interest; kinase inhibitor; macrophage; mutant; neurogenesis; neuron loss; novel; patient population; patient subsets; population based; preclinical study; protein function; reverse genetics; small molecule inhibitor; targeted treatment; tool; transcriptome sequencing; transcriptomics; tumor

Project Summary Sporadic neurodegenerative diseases (NDD) are frequent, heterogeneous and cause severe disabilities in ~30 millions patients worldwide. They represent a major and growing public health challenge, as their causes are unclear and therapeutic options are few. Genetic susceptibility alleles have been identified in a proportion of patients but population-based genetic, transcriptomic, and epigenetic studies have so far provided few significant mechanistic breakthroughs translatable into diagnostic and therapeutic strategies. Among environmental factors it is noted that NDD incidence increases after traumatic brain injury. Nevertheless, the molecular mechanism(s) that underlie neuronal dysfunction and death in these diseases are unclear, which impedes the development of effective treatments. Chronic activation of microglia, the resident macrophage of the brain, is observed at sites of neuronal damage and mutations affecting the function of microglia have been identified in (rare) inherited recessive and dominant neurodegenerative diseases. However, microglia activation in NDD is believed to be in general a reactive process, and its actual pathogenic role has been difficult to resolve in genetic or molecular terms. Despite the important roles of post-zygotic somatic DNA mutations in developmental and tumoral diseases, the possibility that neurodegeneration may be due to deleterious microglia somatic mutants has not been investigated, in large part because of technical limitations, as microglia only represent 5% of brain cells, and develop and maintain locally in the brain. We hypothesize that microglia clonal heterogeneity (mosaicism) is widespread in the human brain and that somatic variants, such as `cancer' mutations (e.g. Kinases gain-of-function) that confer proliferative/activation advantage to microglial clones cause or contribute to neurodegeneration in patients. Our published results from reverse genetic experiments in mice strongly support this hypothesis, and we have obtained preliminary forward genetic evidence that candidate pathogenic clones can be identified in human patients. We have developed protocols to isolate and sequence at high depth microglia nuclei in human brains. Support through the NIH Director's Transformative Research Award at this stage is absolutely needed to allow us to characterize pathogenic clones in a representative sample among the heterogeneous spectrum of NDD, which is an essential task to frame the role of microglia clonality in the neurodegenerative process, and will make possible future studies that will likely focus on specific subsets of patients or on recurrent deleterious clonal events. Results from our project will radically transform our molecular understanding of NDD and provide novel molecular diagnosis in subsets of patients. Because small molecule inhibitors for many of the genes and mutations that confer clonal advantage have been developed by the field of cancer biology, our project should also result in the development of targeted therapies for subsets of NDD.

项目摘要 散发性神经退行性疾病（NDD）是常见的、异质性的， 全球约3000万患者的残疾。它们是一个重大和日益严重的公共卫生挑战， 其原因尚不清楚，治疗选择也很少。遗传易感性等位基因已经在一个 患者的比例，但基于人群的遗传学，转录组学和表观遗传学研究迄今为止， 提供了一些重大的机械突破转化为诊断和治疗策略。 在环境因素中，注意到创伤性脑损伤后NDD发生率增加。 然而，这些疾病中神经元功能障碍和死亡的分子机制是 这阻碍了有效治疗的发展。 小胶质细胞（大脑的常驻巨噬细胞）的慢性激活在神经元细胞的部位被观察到。 影响小胶质细胞功能的损伤和突变已经在（罕见的）遗传隐性和 显性神经退行性疾病然而，NDD中的小胶质细胞激活被认为是一般性的。 反应过程，其实际的致病作用一直难以解决的遗传或分子方面。 尽管合子后体细胞DNA突变在发育和肿瘤发生中起着重要作用， 疾病，神经变性可能是由于有害的小胶质细胞体细胞突变体的可能性还没有 在很大程度上是由于技术限制，因为小胶质细胞只占脑细胞的5%， 并在大脑中局部发育和维持。我们假设小胶质细胞克隆异质性 （嵌合现象）在人脑中广泛存在，体细胞变异，如“癌症”突变， (e.g.激酶获得功能），赋予小胶质细胞克隆增殖/活化优势， 会导致病人的神经退化我们发表的反向遗传实验结果， 小鼠强烈支持这一假设，我们已经获得了初步的遗传证据， 可以在人类患者中鉴定候选致病性克隆。我们已经制定了分离和 在人类大脑中的小胶质细胞核的高深度序列。 在这个阶段，通过NIH主任的变革性研究奖的支持是绝对必要的 使我们能够在异质谱中表征代表性样品中的致病性克隆， NDD，这是一项重要的任务，以框架的作用，小胶质细胞克隆在神经退行性过程中， 并将使未来的研究成为可能，这些研究可能会集中在特定的患者子集或复发性 有害的克隆事件我们项目的结果将从根本上改变我们对NDD的分子理解 并在患者亚群中提供新的分子诊断。因为小分子抑制剂对许多 赋予克隆优势的基因和突变已经由癌症生物学领域开发，我们的 该项目还应导致NDD亚群的靶向治疗的发展。