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

基本信息

批准号：
10183354
负责人：
Frederic Geissmann
金额：
$ 103.62万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
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/10183354
关键词：
Address Adult Affect Age Aging Alleles Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Anatomy Architecture Award Bar Codes 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 anticancer research astrogliosis base brain cell brain tissue developmental disease disability driver mutation 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 single-cell RNA sequencing small molecule inhibitor targeted treatment tool transcriptomics tumor

项目摘要

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.

项目摘要零星的神经退行性疾病（NDD）频繁，异质性并引起严重全球约有300万患者的残疾人。它们代表了一个重大且日益增长的公共卫生挑战，因为它们的原因不清楚，治疗选择很少。遗传敏感性等位基因已在A中鉴定到目前为止提供了很少的重大机械突破，可以转化为诊断和治疗策略。在环境因素中，注意到脑损伤后NDD发病率增加。然而，这些疾病中神经元功能障碍和死亡是基础的分子机制是不清楚，这阻碍了有效治疗的发展。在神经元的部位观察到小胶质细胞的慢性激活小胶质细胞是大脑的常驻巨噬细胞在（罕见的）继承隐性和主要的神经退行性疾病。但是，据信NDD中的小胶质细胞激活通常是A 反应性过程及其实际的致病作用很难以遗传或分子术语解决。尽管后zygotic体细胞DNA突变在发育和肿瘤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突变体引起的研究很大程度上是由于技术局限性的，因为小胶质细胞仅代表5％的脑细胞，并在大脑中局部发展和维护。我们假设小胶质细胞克隆异质性（镶嵌）在人脑中广泛存在，并且体细胞变体，例如“癌症”突变（例如，激酶的功能获得）赋予小胶质克隆的增生/激活优势导致或有助于患者的神经变性。我们发表的来自反向基因实验的结果小鼠强烈支持这一假设，我们获得了初步的远期遗传证据可以在人类患者中鉴定候选病原克隆。我们已经开发了隔离和人脑中高深度小胶质细胞核的序列。在此阶段，通过NIH导演的变革性研究奖的支持绝对需要为了使我们能够表征异质光谱中代表性样本中的致病克隆 NDD是构造小胶质细胞克隆性在神经退行性过程中的作用的重要任务，并将进行未来的研究，可能会集中于患者的特定子集或经常性有害的克隆事件。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子集中提供新的分子诊断。因为许多分子抑制剂癌症生物学领域开发了赋予克隆优势的基因和突变，我们项目还应导致开发NDD子集的靶向疗法。