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: 10631174
• 负责人: Frederic Geissmann
• 金额: $ 91.59万
• 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/10631174
• 关键词: Address; Adult; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Anatomy; Architecture; Award; Bar Codes; Brain; Cancer Biology; Cell Nucleus; Cell Proliferation; Cell physiology; Chronic; Clinical; Clonal Evolution; Clonality; DNA Sequence Alteration; Development; Diagnosis; Diagnostic; Disease; Environmental Risk Factor; Epidemiologic Factors; Epigenetic Process; Erythro; Etiology; Event; Experimental Genetics; Frequencies; Functional disorder; Future; Genes; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic study; Genome; Genomics; Gliosis; Heterogeneity; Histiocytosis; Human; In Vitro; Incidence; Inherited; Laboratories; Longevity; Macrophage; 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; 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; anticancer research; astrogliosis; brain cell; brain tissue; candidate identification; developmental disease; disability; driver mutation; effective therapy; experimental study; gain of function; gastrulation; in vivo; innovation; interest; kinase inhibitor; mosaic; mutant; neurogenesis; neuron loss; novel; patient population; patient subsets; population based; preclinical study; protein function; reverse genetics; single-cell RNA sequencing; small molecule inhibitor; targeted treatment; tool; 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.

项目概要 散发性神经退行性疾病 (NDD) 频繁发生、异质性并导致严重的后果 全球约 3000 万患者患有残疾。它们代表了一项重大且日益严重的公共卫生挑战，因为 其原因尚不清楚，治疗选择也很少。遗传易感性等位基因已在 但迄今为止，基于人群的遗传、转录组和表观遗传学研究尚未发现 提供了一些可转化为诊断和治疗策略的重大机制突破。 在环境因素中，值得注意的是，创伤性脑损伤后 NDD 的发生率会增加。 然而，这些疾病中神经元功能障碍和死亡的分子机制是 不清楚，这阻碍了有效治疗方法的开发。 在神经元部位观察到小胶质细胞（大脑常驻巨噬细胞）的慢性激活 影响小胶质细胞功能的损伤和突变已在（罕见）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通常被认为是 反应过程及其实际致病作用很难用遗传或分子术语来解决。 尽管合子后体细胞 DNA 突变在发育和肿瘤中发挥重要作用 疾病中，神经变性可能是由于有害的小胶质细胞体细胞突变体引起的可能性尚未确定 进行了研究，很大程度上是由于技术限制，因为小胶质细胞仅占脑细胞的 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 （镶嵌现象）在人类大脑中广泛存在，并且体细胞变异，例如“癌症”突变 （例如激酶功能获得）赋予小胶质细胞克隆增殖/激活优势，导致或 导致患者神经退行性变。我们发表的反向遗传实验结果 小鼠强烈支持这一假设，并且我们已经获得了初步的前向遗传证据 可以在人类患者中鉴定出候选致病性克隆。我们已经制定了隔离和 人脑高深度小胶质细胞核的序列。 现阶段绝对需要美国国立卫生研究院院长变革性研究奖的支持 使我们能够表征异质谱中代表性样本中的致病克隆 NDD 是构建小胶质细胞克隆性在神经退行性过程中的作用的一项重要任务， 并使未来的研究可能集中于特定的患者亚群或复发性 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 并为部分患者提供新的分子诊断。因为小分子抑制剂对于许多 赋予克隆优势的基因和突变是由癌症生物学领域开发的，我们的 项目还应导致针对 NDD 子集的靶向疗法的开发。