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ALS病例是遗传的， 其中约17%为单基因病因。其余80%的病例似乎是多因素的， 没有可重现的和/或可靠的遗传关联或内部或外部的环境因素， 鉴定尽管先天免疫的作用已被探索，但一些先天免疫因素 突出显示，它们作为持续炎症反应的引发剂，放大剂或次要标志物的作用并不重要。 在ALS中建立。作为我们对HDL颗粒的货物蛋白的基因变体的研究的结果，我们 确定了杀锥虫的血液和CSF蛋白APOL 1作为影响ALS的有希望的因子， APOL 1是一种分泌型先天免疫因子，由高密度的 脂蛋白颗粒HDL 3和CSF。APOL 1在溶酶体膜中形成通道并破坏血液 大多数锥虫体暴露在临床上是不明显的，因为 在20种已知的锥虫物种中，只有两种，即布氏锥虫和克氏锥虫的变种，是致病性的， 人类非洲出现的looAPOL 1变异等位基因具有拮抗多效性， 抗布氏锥虫耐药菌株，但它们可引起进行性肾病，尤其是SLE， 艾滋病作为共病。我们的假设是，一些APOL 1变异与ALS相关， 血浆和/或CSF中的APOL 1水平可能对易感神经元有毒。APOL 1水平受以下因素影响： 顺式或反式因子。APOL 1基因表达可能通过特定的DNA变异体和/或通过基因突变以顺式调节。 由于暴露于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，我们将使用这些数据来 确定哪些APOL 1变体与ApoL 1血浆浓度和/或mRNA表达相关 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收集额外的患者和对照样本 以及从新患者中前瞻性收集的数据。在选定的样本中，我们将进行检测，以确定 血液可用于确定先前是否已发生锥虫感染以及 可能由于与感染相关的炎症反应而升高的细胞因子。 这是一个新的开拓性的努力，以确定1。APOL 1基因变异和APOL 1水平是否易患 销售。2. Apol 1水平受顺式和可能的反式遗传变异影响的程度 eQTL。3.暴露于锥虫的反式环境因素对Apol 1水平的影响，或 其次是细胞因子如TNF-α、γ-干扰素和1型干扰素或其组合。4.到 建立Apol 1在人类ALS中脆弱神经元的病理学。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病例和对照组，以及广泛的 收集ALS组织和持续的环境暴露数据使我们处于一个独特的位置来执行这一任务 新的建议，从根本上影响SALS的理解和治疗。