Parental imprinting of the X chromosome: effects on neurodegeneration

X 染色体的亲代印记：对神经退行性变的影响

• 批准号: 9340293
• 负责人: RHONDA R VOSKUHL
• 金额: $ 37.95万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340293
• 关键词: Address; Affect; Back; Bone Marrow; Cells; Chimera organism; Chromatin; Clinic; Clinical; Complex; DNA Methylation; Disease; Experimental Autoimmune Encephalomyelitis; Female; Gene Expression; Genes; Genomic Imprinting; Goals; Gonadal Steroid Hormones; Hormone use; Immune response; Immune system; Incidence; Inherited; Laboratories; Lead; Modeling; Mus; Nerve Degeneration; Neuraxis; Public Health; Risk Factors; Role; Severity of illness; Sex Characteristics; Sex Chromosomes; Site-Directed Mutagenesis; Tissues; Translating; X Chromosome; differential expression; disability; irradiation; male; nervous system disorder; novel; paternal imprint; reconstitution; response to injury; tool

Abstract: MS is a complex disease involving both the immune system and the central nervous system (CNS). Females are more susceptible to MS than males, and immune responses are more robust in females. However, females do not demonstrate faster disability progression. Instead, being male is a risk factor for progression. Clearly immune responses and neurodegeneration must be studied independently with respect to sex differences in disease. This proposal will focus on the CNS. Irradiation bone marrow chimeras are a well established tool to manipulate the immune system independently from other tissues. We will use bone marrow chimeras to investigate sex differences in the CNS where there is no sex difference in the immune system. Sex differences will focus on a potential role for sex chromosomes, rather than sex hormones, by using mice that differ in sex chromosomes while having the same gonadal type. By varying sex chromosomes in chimeras reconstituted with a common immune system, one can ascertain the role of sex chromosomes on the CNS response to injury during experimental autoimmune encephalomyelitis (EAE), the most widely used model of MS. Four specific aims will address our overarching hypothesis that maternally inherited X chromosome gene(s) lead to more neurodegeneration in males compared to females, since these genes are expressed more in males who are XmY than females who are XmXp. In aim #1, we will determine how a difference in sex chromosomes affects gene expression in the CNS during EAE. In aim #2, we will determine how maternal versus paternal imprinting of the X chromosome affects DNA methylation and chromatin accessibility of genes in the CNS during EAE. In aim #3, we will use a CNS cell specific gene expression approach (RiboTag) to identify which sex chromosome genes differ in which cell in the CNS during EAE. In aim #4. We will determine the functional significance of sex chromosome genes that are differentially expressed in CNS cells during EAE. Together the above aims will identify sex chromosome gene(s) that lead to worse clinical and neuropathological disease. These findings will reveal new targets with the ultimate goal of finding a treatment to halt or slow neurodegeneration and disability progression in MS and potentially other neurological diseases.

摘要： MS是一种同时涉及免疫系统和中枢神经系统(CNS)的复杂疾病。 女性比男性更容易患多发性硬化症，女性的免疫反应更强劲。 然而，女性并没有表现出更快的残疾进展。相反，男性是一个危险因素。 进步。显然，免疫反应和神经退行性变必须独立研究 疾病的性别差异。 这项提案将把重点放在CNS上。辐射骨髓嵌合体是一种成熟的工具 独立于其他组织操纵免疫系统。我们将使用骨髓嵌合体来 在免疫系统没有性别差异的情况下，研究中枢神经系统的性别差异。性别差异 将通过使用不同性别的小鼠，专注于性染色体的潜在作用，而不是性激素 染色体上有相同的性腺类型。通过重组嵌合体中不同的性染色体 有了共同的免疫系统，我们就可以确定性染色体在中枢神经系统对 实验性自身免疫性脑脊髓炎(EAE)期间的损伤，这是四种MS中使用最广泛的模型 具体目标将解决我们的首要假设，即母亲遗传X染色体基因(S) 导致男性比女性更多的神经变性，因为这些基因表达得更多 男性是XmY，而女性是XmXp。在目标1中，我们将确定性别差异 在EAE过程中，染色体影响中枢神经系统的基因表达。在目标2中，我们将确定母性 X染色体印记与父系印记对DNA甲基化和染色质可及性的影响 在EAE期间，在中南半球。在目标3中，我们将使用CNS细胞特异性基因表达方法(RiboTag)来 确定在EAE期间中枢神经系统中的哪个细胞中哪些性染色体基因不同。在目标4中，我们将确定 EAE期间中枢神经系统差异表达的性染色体基因的功能意义。 综合上述目标，将确定导致更糟糕的临床和性染色体基因(S) 神经病理性疾病。这些发现将揭示新的靶点，最终目标是找到治疗方法。 阻止或减缓多发性硬化症和潜在的其他神经系统疾病的神经退行性变和残疾进展。