Creating a foundation for personalized age- and sex-based immune-targeted therapies from an ALS longitudinal cohort by identifying peripheral and central immune signatures

通过识别外周和中枢免疫特征，为 ALS 纵向队列中基于年龄和性别的个性化免疫靶向治疗奠定基础

• 批准号: 10403433
• 负责人: Stephen Goutman
• 金额: $ 63.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403433
• 关键词: ALS patients; Address; Affect; Age; Amyotrophic Lateral Sclerosis; Animals; Area; Biological Markers; Blood; Blood specimen; CD4 Positive T Lymphocytes; Cell Count; Cells; Cessation of life; Characteristics; Clinical; Clinical Trials; Coculture Techniques; Data; Data Set; Development; Disease; Disease Progression; Estrogens; Foundations; Goals; Gonadal Steroid Hormones; Hormones; Human; Immune; Immune Targeting; Immune response; Immune system; Immunomodulators; Immunophenotyping; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Inflammation; Inflammatory; Knowledge; Link; Literature; Longitudinal Studies; Longitudinal cohort; Mediating; Michigan; Mission; Motor Neuron Disease; Natural Killer Cells; Nervous system structure; Neurons; Outcome; Pathway interactions; Patients; Peripheral; Persons; Phenotype; Population; Positron-Emission Tomography; Prostitution; Public Health; Recording of previous events; Regulatory T-Lymphocyte; Research; Sampling; Severity of illness; Survival Rate; System; Testosterone; Time; Toxic effect; Tweens; United States National Institutes of Health; Universities; amyotrophic lateral sclerosis therapy; base; biobank; cohort; cytotoxicity; deep neural network; design; drug development; drug repurposing; effective therapy; immune function; in vivo; innovation; insight; interest; knowledge base; nervous system disorder; neuroinflammation; neurotoxicity; neutrophil; new therapeutic target; peripheral blood; personalized medicine; personalized therapeutic; predictive modeling; sex; targeted treatment; therapeutic development; therapeutic target; transcriptome sequencing

ABSTRACT The immune system contributes to amyotrophic lateral sclerosis (ALS) progression and survival, and therapies to target the immune system are of burgeoning interest. However, the changes in the immune system during the course of ALS and the sex-specific alterations in immune function warrant a more in depth analysis in order to develop personalized ALS therapies and biomarkers. The long-term goals are to harness the immune sys- tem’s potential to slow and stop the progression of ALS. The overall objective is to determine how peripheral immune profiles, sex, age, and sex hormones, link to neuronal damage, neuroinflammation, and ALS progres- sion and survival. The central hypothesis is that peripheral immune profiles are an important pathophysiologic agent of ALS progression and survival; that sex, age and sex hormone levels impact these profiles; and that insight into ALS patient-specific immune profiles will yield new drug targets and therapeutic windows. Our ra- tionale is that linking patient-specific immune cell profiles to ALS progression and survival will facilitate person- alized immunomodulatory therapeutic development for ALS and identify potential treatment windows. The cen- tral hypothesis will be pursued with three aims: 1) Identify specific immune profiles that associate with ALS pro- gression and survival rates.; 2) Evaluate the effects of sex hormones on ALS immune profiles, progression, and survival; and 3) Identify immune profiles and corresponding cellular pathways that are most toxic to neu- rons and that associate with central inflammation. In Aim 1 longitudinal immunophenotyping of peripheral blood samples from ALS subjects will generate composite immune profiles that will then be linked to ALS subject characteristics, progression, and survival. Aim 2 will determine if observed sex-dependent associations be- tween immune profiles and ALS progression and survival are mediated by sex hormones, as sex hormones can alter immune profiles. Aim 3 will enrich a cohort of ALS subjects by immune profile clusters; their periph- eral immune populations will be analyzed using 1) RNA-seq and 2) cell toxicity studies via co-cultures with iPSC-derived neurons; subjects will also have positron emission tomography (PET) imaging to quantify central neuroinflammation. Datasets will be synthesized to build prediction models and create deep neural networks capable of associating immune profiles with sex, age, disease severity, progression, and survival The research proposed is innovative, in the applicants’ opinion, because it rigorously examines the effects of sex, age, and sex hormone levels on immune cells and ALS progression and survival in a longitudinal study. It also accounts for the interactions between immune cells by forming immune profiles for individual subjects and assesses how specific profiles associate with dysregulated pathways, cytotoxicity, and neuroinflammation. The proposed re- search is significant because it will provide critical data on the distinct immune profiles and pathways associ- ated with ALS progression and survival in a sex-, age- and sex hormone- specific fashion.

抽象的 免疫系统有助于肌萎缩性侧面硬化症（ALS）进展和生存，疗法 靶向免疫系统具有野蛮的兴趣。但是，免疫系统的变化 ALS的过程和免疫功能的性别特异性改变需要更深入的分析 开发个性化的ALS疗法和生物标志物。长期目标是利用免疫系统 - TEM有可能减慢和阻止ALS的进展。总体目标是确定外围 免疫特征，性别，年龄和性马，与神经元损害，神经炎症的联系，ALS的进展 - sion和生存。中心假设是外周免疫特征是重要的病理生理学 ALS进展和生存的代理；性别，年龄和性激素水平会影响这些特征。那 洞悉ALS患者特异性免疫特征将产生新的药物靶标和治疗窗口。我们的ra- tionale是，将患者特异性免疫元素与ALS的进展和生存联系起来将有助于人 - ALS的二聚体免疫调节热发育并确定潜在的治疗窗口。 cen- TRAL假设将以三个目的进行：1）确定与ALS促进的特定免疫特征 问候和生存率。 2）评估性恐怖对ALS免疫特征，进展， 和生存； 3）确定对Neu-最具毒性的免疫特征和相应的细胞途径 罗恩斯和那个与中央感染有关的。在AIM 1外周血的纵向免疫结构 来自ALS受试者的样本将产生复合免疫特征，然后将其链接到ALS受试者 特征，发展和生存。 AIM 2将确定观察到的性别依赖性关联是否是 推文免疫特征，ALS的进展和生存是由性激素介导的，作为性激素 可以改变免疫特征。 AIM 3将通过免疫轮廓簇丰富一群ALS受试者。他们的外围 将使用1）RNA-seq和2）通过与共同培养的细胞毒性研究对ERA免疫筛查进行分析 IPSC衍生的神经元；受试者还将具有正电子发射断层扫描（PET）成像以量化中央 神经炎症。数据集将被合成以构建预测模型并创建深层神经元网络 能够将免疫特征与性别，年龄，疾病严重程度，进展和生存相关联 申请人认为，拟议的是创新的，因为它严格研究了性，年龄和 在一项纵向研究中，免疫细胞和ALS进展和存活的性骑士水平。它也是帐户 对于免疫细胞之间的相互作用，通过形成单个受试者的免疫特征和评估如何 与途径失调，细胞毒性和神经炎症相关的特定轮廓。拟议的重新 搜索很重要，因为它将提供有关独特的免疫特征和关联途径的关键数据 在性别，年龄和性激素特定的时尚中以ALS的进展和生存为生。