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: 10250537
• 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 2022-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250537
• 关键词: Adaptive Immune System; Advisory Committees; Animals; Antigens; Autoimmune; Autoimmune Diseases; 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; Prognosis; 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; diagnostic platform; 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; 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的自身免疫性疾病，临床上很难处理，因为它是 以不可预测的缓解和复发时期为特点。如果这种疾病能够得到充分的监测， 药物可能会进行干预，以防止损害，降低复发率和总体进展。理想情况下， 重复地对中枢神经系统进行活组织检查是可能的，但这太具有挑战性/病态，没有实用价值。 在这里，我们提出了一种利用组织工程学原理来开发免疫学利基的方法。 (In)在体内，以便能够收获生理上相关的免疫种群。这项工作的中心假设是 INS可以被创建来反映先天和/或适应性免疫系统与 中枢神经系统。此外，我们假设，惯性导航系统将提供一个位置，其中一个非侵入式光学传感器的 多发性硬化症是可以植入的。目标1将测试植入材料的FBR可以 被利用来创建反映中枢神经系统先天免疫的IN，并将动态监测 这一利基的形成。在疾病诱导和治疗期间，在适当的时间点切除脚手架 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 能够确定老鼠是否患病或健康的签名。目标2(K99)将利用特定的 为疾病进展的生物标记物建立非侵入性传感器的抗原结合肽。 特异结合疾病生物标记物的荧光团标记的多肽将被并入到聚乙二醇酯中 水凝胶，将经过改造，使所需抗原的结合能够通过FRET进行检测。 这些传感器将被结合到IN的小孔中，以实现对MS Aim 3(R00)的非侵入性监测 将通过在中枢神经系统中加入抗原来开发反映中枢神经系统适应性免疫群体的INS 脚手架。本部分将创建一个非侵入式传感器和反映自适应的多变量特征 代谢物内的免疫变化和利用先天和适应性INS来研究机制 关于多发性硬化症发育过程中的先天自适应串扰的问题，这些研究将创造 精心设计的免疫学利基和非侵入性传感器，能够创建增强的诊断， 无安乐死的预后、治疗监测和纵向免疫学研究。 这项工作是免疫学和生物材料的交叉点，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。这个 申请者在生物材料、组织工程和宿主反应方面有丰富的经验，但要求 在免疫学、计算分析和生物传感器设计/验证方面的进一步培训。这一奖项和 咨询委员会将为申请人提供工具和专业知识，以开始他的独立职业生涯 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自适应串扰中未回答的问题。