Immulogical Niches and Non-invasive Biosensors for Autoimmune Monitoring

用于自身免疫监测的免疫利基和非侵入性生物传感器

• 批准号: 10704726
• 负责人: Aaron Harvey Morris
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704726
• 关键词: Adaptive Immune System; Advisory Committees; Antigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Award; Binding; Biocompatible Materials; Biological Markers; Biopsy; Biosensor; Clinical Management; Computer Analysis; Demyelinations; Detection; Development; Diagnostic; Disease; Disease Progression; Disease remission; Engineering; Euthanasia; Fluorescence Resonance Energy Transfer; Gene Chips; Gene Expression; Harvest; Hydrogels; Immune; Immune response; Immunologics; Immunology; Implant; Label; Location; Machine Learning; Monitor; Multiple Sclerosis; Mus; Natural Immunity; Peptides; Pharmaceutical Preparations; Physiological; Population; Relapse; Research Personnel; Techniques; Testing; Time; Tissue Engineering; Training; Validation; Work; antigen binding; career; design; experience; fluorophore; immunoengineering; implant material; in vivo; non-invasive monitor; novel diagnostics; optical sensor; prevent; prognostic; scaffold; sensor; tool

Multiple sclerosis is a demyelinating autoimmune disease that is difficult to manage clinically, because it is characterized by unpredictable periods of remission and relapse. If the disease could be adequately monitored, it is possible drugs could intervene to prevent damage, reducing rates of relapse and overall progression. Ideally, it would be possible to repeatedly biopsy the CNS for monitoring, but this is too challenging/morbid to have utility. Herein, we propose an approach that harnesses tissue engineering principles to develop an immunological niche (IN) in vivo to enable harvest of physiologically relevant immune populations. The central hypothesis of this work is that INs can be created to reflect aspects of the innate and/or adaptive immune system that correlate with the CNS. Furthermore, we hypothesize that INs will provide a location into which a non-invasive optical sensor of multiple sclerosis can be implanted. Aim 1 will test the hypothesis that the FBR to implanted materials can be harnessed to create an IN reflective of innate immunity in the CNS and will dynamically monitor the formation of this niche. Scaffolds will be excised at appropriate time points during disease induction and analyzed with high-throughput gene expression arrays, scRNAseq, and machine learning to develop multivariate signatures capable of determining whether a mouse is diseased or healthy. Aim 2 (K99) will harness specific antigen-binding peptides to build noninvasive sensors for biomarkers of disease progression. Fluorophore-labeled peptides that specifically bind biomarkers of disease will be incorporated into PEG hydrogels which will be engineered such that the binding of the desired antigen will enable detection via FRET. These sensors will be incorporated into the pores of the IN to enable non-invasive monitoring of MS. Aim 3 (R00) will develop INs reflective of adaptive immune populations in the CNS, by incorporating antigens within the scaffolds. This section will create a non-invasive sensor and multivariate signature reflective of adaptive immune changes within the surrogates and harness both innate and adaptive INs to investigate mechanistic questions about innate-adaptive crosstalk in the development of MS. Taken together these studies will create engineered immunological niches and non-invasive sensors that enable the creation of enhanced diagnostics, prognostics, treatment monitors, and longitudinal immunology studies without euthanasia. This work is at the intersection of immunology and biomaterials and will require biomaterials synthesis, scRNAseq, computational analysis, tissue engineering, immunology, and biosensor design and validation. The applicant has significant experience in biomaterials, tissue engineering, and the host response, but requires further training in immunology, computational analysis, and biosensor design/validation. Both this award and the advisory committee will provide the applicant tools and expertise to begin his career as an independent investigator. Furthermore, this work will develop new diagnostics, new techniques useful to the field as a whole, and contribute to an understanding of unanswered questions in innate-adaptive crosstalk in autoimmunity.

多发性硬化症是一种脱髓鞘自身免疫性疾病，临床上很难管理，因为它是 其特征在于不可预测的缓解和复发期。如果这种疾病能得到充分的监测， 有可能药物可以干预以防止损害，降低复发率和总体进展。理想情况下， 可以重复地对CNS进行活检以进行监测，但是这太具有挑战性/病态而没有实用性。 在此，我们提出了一种利用组织工程原理来开发免疫生态位的方法 (IN)以能够收获生理学上相关的免疫群体。这项工作的核心假设是 可以产生IN以反映与免疫缺陷相关的先天性和/或适应性免疫系统的方面。 CNS。此外，我们假设，IN将提供一个位置，其中一个非侵入性光学传感器， 多发性硬化症是可以植入的目标1将检验植入材料的FBR可以 被利用来创建反映CNS中先天免疫的IN，并将动态监测 形成了这个niche。在疾病诱导期间的适当时间点切除支架， 使用高通量基因表达阵列、scRNAseq和机器学习进行分析， 能够确定小鼠是否患病或健康的特征。目标2（K99）将利用特定的 抗原结合肽来构建疾病进展生物标志物的非侵入性传感器。 特异性结合疾病生物标志物的荧光团标记的肽将被掺入PEG中。 水凝胶，其将被工程化，使得所需抗原的结合将能够通过FRET进行检测。 这些传感器将被纳入IN的孔中，以实现MS的无创监测。Aim 3（R 00） 将通过将抗原掺入 脚手架。本节将创建一个非侵入式传感器和反映自适应的多变量签名 免疫变化的替代品和利用先天性和适应性IN来研究机制 关于多发性硬化症发展中先天自适应串扰的问题。综合起来，这些研究将创建 工程免疫小生境和非侵入性传感器，使增强诊断的创建， 无安乐死的免疫学、治疗监测和纵向免疫学研究。 这项工作是在免疫学和生物材料的交叉点，将需要生物材料的合成， scRNAseq、计算分析、组织工程、免疫学和生物传感器设计和验证。的 申请人在生物材料、组织工程和宿主反应方面具有丰富的经验，但需要 免疫学、计算分析和生物传感器设计/验证方面的进一步培训。这个奖项和 咨询委员会将提供申请人的工具和专业知识，开始他的职业生涯作为一个独立的 调查员此外，这项工作将开发新的诊断方法，对整个领域有用的新技术， 并有助于理解自身免疫中先天适应性串扰中的未回答问题。