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.

肌萎缩性外侧硬化症（ALS）是一种致命的神经退行性疾病。 20％的ALS病例是遗传的 在大约17％的情况下发现单基因原因。其余80％的案件似乎是多因素的，并且 内部或外部的可重现和/或稳健的遗传关联或环境因素（S）一直是 确定。尽管已经探索了先天免疫的作用和一些先天免疫因素 强调，他们作为持续炎症反应的发起人，放大器或次要标记的作用不是 建立在ALS中。作为我们研究HDL粒子货物蛋白基因变异的结果，我们 鉴定锥虫血液和CSF蛋白Apol1是一种有前途的药物，影响了ALS 对环境因素敏感。APOL1是由高密度携带的分泌的先天免疫史因素 脂蛋白颗粒HDL3和CSF。 Apol1在溶酶体膜中形成通道并破坏血液 寄生虫的溶酶体功能，杀死它。大多数锥虫体暴露在临床上都是不可能的，因为 在二十种已知的锥虫物种中，只有两个，T.Brucei和T.Cruzei的品种对 人类。 looapol1的变体等位基因在非洲出现，具有拮抗性多效性，有效 抵抗乳杆菌的抗性菌株，但它们可能引起渐进性肾脏疾病，尤其是在SLE和 艾滋病作为同名。我们的假设是某些APOL1变体与ALS相关，因为升高 血浆和或CSF中的APOL1水平可能对易感神经元有毒。 apol1级别受IN的影响 顺式或反式因素。 APOL1基因表达可能通过特定的DNA变异和/或在顺式中调节 由于暴露于锥虫或细胞因子（例如干扰素或其他）而引起的反式，尚未鉴定 环境因素。我们有具有相关流行病学数据的患者样本 确定哪些APOL1变体与血浆浓度APOL1和/或mRNA表达相关 在患者来源的淋巴细胞中。我们还将从我们自己的收藏中额外的病人和控制样本 以及那些从新患者那里收集的。在选定的样本中，我们将运行分析以确定是否 血液可用于确定是否发生了先前的锥虫感染以及 由于与感染相关的炎症反应可能会升高的细胞因子。 这是确定1的新开创性的努力。Apol1遗传变异和Apol1水平是否容易 萨尔。 2。在顺式和反式遗传变体中影响APOL1水平的程度 作为eqtls。 3。在反式环境因素中对APOL1水平的影响，暴露于锥虫或 其次，由细胞因子（例如TNF-α，γ-间隙和1型干扰素）或其组合。 4 在人类ALS中脆弱神经元的病理中建立APOL1。我们承诺的初步数据， 经验丰富的团队，并严格定义了年龄匹配的ALS案件和对照组的队列 ALS组织和正在进行的环境暴露数据的收集使我们处于独特的位置 从根本上实现对萨尔及其治疗的理解的新建议。