A novel innate immunity risk factor for amyotrophic lateral sclerosis

肌萎缩侧索硬化症的新先天免疫危险因素

• 批准号: 10220811
• 负责人: TEEPU SIDDIQUE
• 金额: $ 30万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220811
• 关键词: novel; innate; immunity; risk; factor

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. 20% of ALS cases are genetic, with monogenic causes identified in about 17%. The remaining 80% of cases appear to be multifactorial, and no reproducible and/or robust genetic association or environmental factor(s), internal or external, have been identified. Although the role of innate immunity has been explored and some innate immunity factors highlighted, their role as initiators, amplifiers or secondary markers of an ongoing inflammatory response is not established in ALS. As the result of our study of gene variants of cargo proteins of the HDL particle, we identified the trypanocidal blood and CSF protein, APOL1, as a promising agent affecting ALS that is also sensitive to environmental factors.APOL1 is a secreted innate immunity factor carried by the high-density lipoprotein particle HDL3and CSF. APOL1 forms a channel in the lysosomal membrane and disrupts the blood borne parasite's lysosomal function, killing it. Most trypanasome exposures are clinically inapparent because only two of the twenty known trypanosome species, varieties of T.brucei and T.cruzei, are pathogenic to humans. Variant alleles of looAPOL1 emerged in Africa with the property of antagonistic pleiotropy, effective against resistant strains of T.brucei, but they can cause progressive kidney disease especially with SLE and AIDS as co-morbities. Our hypothesis is that some APOL1 variants are associated with ALS because elevated APOL1 levels in plasma and or CSF can be toxic to susceptible neurons. APOL1 levels are influenced by in cis or in trans factors. APOL1 gene expression is likely regulated in cis by specific DNA variants and/or by in trans due to exposure to trypanosomes or to cytokines such as the interferons or other, yet to be identified, environmental factors. We have patient samples with associated epidemiological data that we will use to determine which APOL1 variants are correlated with plasma concentrations of ApoL1 and/or mRNA expression in patient-derived lymphoblasts. We also will additional patient and control samples from our own collection and those collected prospectively from new patients. In selected samples we will run assays to determine if blood can be used to determine whether a prior trypansomal infection has occurred as well as levels of cytokines that may be elevated due to inflammatory responses related to infection. This is a novel pioneering effort to ascertain 1. Whether APOL1 genetic variants and APOL1 levels predispose to SALS. 2. The extent to which Apol1 levels are affected by in cis and possibly in trans genetic variantsacting as eQTLs. 3. The effect on Apol1 levels by in trans environmental factors of exposure to trypanosomes, or secondarily by cytokines such as TNF-α, γ-interferon and type 1 interferons, or a combination thereof. 4. To establish Apol1 in the pathology of vulnerable neurons in human ALS. Our promising preliminary data, experienced team, and rigorously defined cohort of age-matched ALS cases and controls and extensive collection of ALS tissue and ongoing environment exposure data puts us in a unique position to carry out this novel proposal to fundamentally effect the understanding of SALS and its treatment.

肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病。20%的肌萎缩侧索硬化症病例是遗传的， 单基因致病约占17%。其余80%的病例似乎是多因素的，并且 没有可复制和/或强大的遗传关联或环境因素(S)，无论是内部的还是外部的 确认身份。虽然先天免疫的作用已经被探索，但一些先天免疫因素 强调，它们作为正在进行的炎症反应的启动者、扩张者或辅助标记物的作用不是 建立在肌萎缩侧索硬化症。作为我们对高密度脂蛋白颗粒货运蛋白基因变异的研究的结果，我们 确定杀锥虫血和脑脊液蛋白APOL1是一种有希望的影响ALS的药物，它也是 对环境因素敏感。APOL1是一种分泌型天然免疫因子，由高密度 脂蛋白颗粒HDL3和脑脊液。APOL1在溶酶体膜上形成通道，扰乱血液 携带寄生虫的溶酶体功能，杀死它。大多数锥虫暴露在临床上是不明显的，因为 在已知的20种锥虫中，只有两种是布鲁氏锥虫和克氏锥虫的变种，对 人类。非洲出现的loAPOL1变异等位基因具有拮抗多效性，有效 抗布鲁氏毛滴虫耐药株，但它们可导致进行性肾脏疾病，特别是SLE和 艾滋病是一种共病。我们的假设是，一些APOL1变异与ALS有关，因为 血浆和/或脑脊液中的APOL1水平可能会对敏感神经元产生毒性。载脂蛋白1水平受In影响 顺式或反式因子。Apol1基因在顺式细胞中的表达可能受特定的dna变异体和/或in的调节。 由于接触锥虫或细胞因子，如干扰素或其他，尚未确定， 环境因素。我们有患者样本和相关的流行病学数据，我们将利用这些样本 确定哪些APOL1变体与APOL1和/或mRNA表达的血浆浓度相关 在患者来源的淋巴母细胞中。我们还将从我们自己的收集中增加患者和对照样本 以及那些预期从新患者那里收集的数据。在选定的样本中，我们将进行化验以确定 血液可以用来确定以前是否发生过锥体感染，以及 由于与感染相关的炎症反应而可能升高的细胞因子。 这是一项新的开创性工作，旨在确定1.载脂蛋白1基因变异和载脂蛋白1水平是否易患 敬萨尔斯。2.载脂蛋白1水平受顺式和可能的反式遗传变异影响的程度 作为eQTL。3.接触锥虫的跨环境因素对APOL1水平的影响，或 其次是通过细胞因子，如肿瘤坏死因子-α，γ-干扰素和1型干扰素，或其组合。4.至 建立APOL1在人ALS易损神经元病理学中的作用。我们有希望的初步数据， 经验丰富的团队，严格定义的年龄匹配的ALS病例和对照队列，以及广泛的 收集肌萎缩侧索硬化症组织和持续的环境暴露数据使我们处于执行这一任务的独特位置 从根本上影响对SALS及其治疗的理解的新建议。