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: 10054726
• 负责人: Aaron Harvey Morris
• 金额: $ 9.18万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054726
• 关键词: Adaptive Immune System; Advisory Committees; Animals; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Award; Binding; Biocompatible Materials; Biological Markers; Biopsy; Biosensor; Cells; Clinical; Clinical Management; Computer Analysis; Data; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic Specificity; Disease; Disease Progression; Disease remission; Distal; Elderly; Engineering; Euthanasia; Event; Experimental Autoimmune Encephalomyelitis; Extravasation; Flare; Fluorescence Resonance Energy Transfer; Foreign Bodies; Future; Gel; Gene Chips; Gene Expression; Goals; Harvest; Health; Heterogeneity; Homing; Hydrogels; Immune; Immune response; Immune system; Immunologics; Immunology; Implant; Label; Location; Machine Learning; Malignant Neoplasms; Measurement; Measures; Monitor; Morbidity - disease rate; Multiple Sclerosis; Mus; Myelin; Natural Immunity; Neoplasm Metastasis; Neuraxis; Non-Invasive Cancer Detection; Obesity; Onset of illness; Organ; Pathogenesis; Pathologic; Pathology; Patients; Peptides; Phage Display; Phagocytes; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Population; Pre-Clinical Model; Proteins; Proteolipids; Relapse; Relapsing-Remitting Multiple Sclerosis; Research; Research Personnel; Site; System; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic Intervention; Time; TimeLine; Tissue Engineering; Tissue Harvesting; Tissues; Training; Tumor-infiltrating immune cells; Validation; Walking; Work; adaptive immune response; adaptive immunity; antigen binding; base; caprolactone; career; comorbidity; cytokine; design; disability; experience; fluorophore; glucose monitor; imaging approach; immunoengineering; immunological status; implant material; implanted sensor; improved; in vivo; interest; liquid biopsy; member; mouse model; neoplastic cell; non-invasive monitor; novel diagnostics; novel strategies; optical sensor; outcome forecast; personalized approach; preclinical study; prevent; prognostic; response; scaffold; sensor; small molecule; subcutaneous; 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，临床上难以治疗，因为它 其特点是不可预测的缓解期和复发期。如果能够充分监测该疾病， 药物可能会进行干预以防止损害，降低复发率和总体进展率。理想情况下， 可以反复对中枢神经系统进行活检以进行监测，但这太具有挑战性/病态性而没有实用性。 在此，我们提出了一种利用组织工程原理来开发免疫学生态位的方法 (IN) 体内，以收获生理相关的免疫群体。本工作的中心假设 是可以创建 IN 来反映与先天性和/或适应性免疫系统相关的方面 中枢神经系统。此外，我们假设智能网将提供一个位置，其中非侵入式光学传感器 多发性硬化症可以植入。目标 1 将检验植入材料的 FBR 可以 被用来创建反映中枢神经系统先天免疫的 IN，并将动态监测 这个利基的形成。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，以开发多变量 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 抗原结合肽构建用于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肽将被整合到 PEG 中 水凝胶将被设计成与所需抗原结合，从而能够通过 FRET 进行检测。 这些传感器将被纳入 IN 的孔隙中，以实现 MS 的非侵入性监测。目标 3 (R00) 将通过将抗原纳入其中来开发反映中枢神经系统适应性免疫群体的IN 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 替代者体内的免疫变化，并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适应性串扰的问题。这些研究综合起来将创建 工程免疫学生态位和非侵入性传感器能够创建增强的诊断， 无需安乐死的预后、治疗监测和纵向免疫学研究。 这项工作处于免疫学和生物材料的交叉点，需要生物材料合成， scRNAseq、计算分析、组织工程、免疫学以及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，但要求 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。无论是这个奖项还是 咨询委员会将为申请人提供工具和专业知识，以开始他作为独立人士的职业生涯 研究者。此外，这项工作将开发对整个领域有用的新诊断、新技术， 并有助于理解自身免疫中先天适应性串扰中未解答的问题。