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: 10006773
• 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/10006773
• 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 病例是遗传性的， 大约 17% 的人发现单基因原因。其余 80% 的病例似乎是多因素造成的，并且 没有可重复的和/或强大的遗传关联或内部或外部的环境因素 确定。尽管先天免疫的作用已经被探索并且一些先天免疫因素 强调指出，它们作为持续炎症反应的引发剂、放大器或次要标志物的作用并不重要。 在 ALS 中建立。作为我们对 HDL 颗粒货物蛋白基因变异的研究结果，我们 确定了杀锥虫血液和脑脊液蛋白 APOL1 是一种有前途的影响 ALS 的药物，而且 对环境因素敏感。APOL1是高密度细胞携带的分泌型先天免疫因子 脂蛋白颗粒HDL3和CSF。 APOL1 在溶酶体膜中形成通道并扰乱血液 携带寄生虫的溶酶体功能，将其杀死。大多数锥虫暴露在临床上是不明显的，因为 二十种已知的锥虫种类中，只有两种，即布氏锥虫和克氏锥虫，对锥虫有致病性。 人类。非洲出现了 looAPOL1 的变异等位基因，具有拮抗多效性，有效 对抗 T.brucei 的耐药菌株，但它们可引起进行性肾病，尤其是 SLE 和 艾滋病作为合并症。我们的假设是，一些 APOL1 变异与 ALS 相关，因为升高 血浆和/或脑脊液中的 APOL1 水平可能对易感神经元有毒。 APOL1 水平受以下因素影响 顺式或反式因子。 APOL1 基因表达可能受特定 DNA 变体和/或 in 顺式调节 由于接触锥虫或细胞因子（例如干扰素或其他尚未确定的细胞因子）而发生反式， 环境因素。我们拥有带有相关流行病学数据的患者样本，我们将用它们来 确定哪些 APOL1 变体与 ApoL1 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添加额外的患者和对照样本 以及前瞻性地从新患者身上收集的数据。在选定的样本中，我们将进行检测以确定是否 血液可用于确定先前是否发生过锥虫感染以及锥虫水平 由于感染相关的炎症反应可能导致细胞因子升高。 这是一项新颖的开创性工作，旨在确定 1. APOL1 基因变异和 APOL1 水平是否易诱发 到销售服务处。 2. Apol1 水平受顺式和可能的转基因变异影响的程度 作为 eQTL。 3. 暴露于锥虫的反式环境因素对 Apol1 水平的影响，或 其次是细胞因子，例如TNF-α、γ-干扰素和1型干扰素或其组合。 4. 至 建立 Apol1 在人类 ALS 脆弱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 ALS 组织和持续的环境暴露数据使我们处于执行此任务的独特位置 从根本上影响对 SALS 及其治疗的理解的新颖提议。