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; 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的自身免疫性疾病，很难在临床上进行治疗，因为它是 以不可预测的缓解和复发期为特征。如果可以对该疾病进行充分的监测， 可能药物可以干预以防止损害，降低复发率和整体进展。理想情况下， 可以反复进行中枢神经系统进行监测，但这太具有挑战性/病态了，无法拥有效用。 本文中，我们提出了一种利用组织工程原则发展免疫学位的方法 （在）体内能够收获生理相关的免疫群体。这项工作的中心假设 是可以创建INS来反映与先天和/或适应性免疫系统的各个方面 CNS。此外，我们假设INS将提供一个非侵入性光学传感器的位置 可以植入多发性硬化症。 AIM 1将检验FBR到植入材料的假设可以 要利用创建一种反映中枢神经系统中的先天免疫力，并将动态监视 这种利基的形成。在疾病诱导期间，将在适当的时间点切除脚手架，并 用高通量基因表达阵列，SCRNASEQ和机器学习以开发多变量分析 能够确定小鼠是患病还是健康的特征。目标2（K99）将特定利用 抗原结合肽为疾病进展的生物标志物构建无创的传感器。 特异性结合疾病的生物标志物的荧光团标记的肽将纳入PEG 将要设计的水凝胶使所需抗原的结合将通过FRET检测。 这些传感器将被合并到IN的孔中，以实现MS的非侵入性监测。目标3（R00） 通过将抗原掺入中，会产生反映中枢神经系统中适应性免疫种群的INS 脚手架。本节将创建一个反映自适应的非侵入性传感器和多元签名 替代物和线索内的免疫变化与天生和适应性INS一起研究机理 关于MS的发展中有关先天自适应串扰的问题。结合这些研究将创造 工程的免疫利基和非侵入性传感器，能够创建增强的诊断， 没有安乐死的预后，治疗监测器和纵向免疫学研究。 这项工作是在免疫学和生物材料的交汇处，需要生物材料合成， SCRNASEQ，计算分析，组织工程，免疫学和生物传感器设计和验证。这 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/验证的进一步培训。这个奖项和 咨询委员会将提供申请人工具和专业知识，以开始他的职业生涯 研究者。此外，这项工作将开发新的诊断，新技术对整个领域有用， 并有助于理解自身免疫中先天自适应的串扰中未解决的问题。