Immulogical Niches and Non-invasive Biosensors for Autoimmune Monitoring; Diversity Supplement

用于自身免疫监测的免疫生态位和非侵入性生物传感器；

• 批准号: 10842016
• 负责人: Aaron Harvey Morris
• 金额: $ 5.86万
• 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/10842016
• 关键词: Antigen Presentation; Antigens; Autoimmune; Autoimmune Diseases; Biocompatible Materials; Biopsy; Biosensor; Cell Nucleus; Cells; Clinical Management; Demyelinations; Development; Diagnosis; Diagnostic; Dimerization; Disease; Disease Progression; Disease remission; Engineering; Euthanasia; Experimental Autoimmune Encephalomyelitis; Goals; Harvest; Immune; Immunologics; Immunology; Implant; Ligand Binding; Ligands; Luminescent Proteins; Measurement; Monitor; Multiple Sclerosis; Myelin; Onset of illness; Optics; Pathogenicity; Pharmaceutical Preparations; Phase; Physiological; Population; Proteins; Relapse; Research; Signal Transduction; Site; System; Testing; Tissue Engineering; Transgenes; Work; adaptive immune response; cytokine; immune cell infiltrate; immunoengineering; in vivo; mouse model; prevent; prognostic; receptor; response; scaffold; sensor; subcutaneous; synthetic biology; tool; transcription factor

Multiple sclerosis (MS) 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. In the K99 phase of my work, we developed an approach that harnesses tissue engineering principles to develop an immunological niche (IN) in vivo to enable harvest of physiologically relevant immune populations. Furthermore, we developed synthetic biology-based biosensors that produce optically detectable signals in response to specific ligands. In the R00 phase, I propose to continue my work in this space, by testing the biosensors in vivo, engineering INs that specifically enrich pathogenic populations of adaptive immune cells, and leverage the combination biosensors and engineered IN to monitor expression of cytokines during antigen presentation in vivo. In Aim 2 (in progress) we developed three different engineered receptor systems that upon binding ligand dimerize and liberate an engineered transcription factor (TF). This TF traffics to the nucleus and induces expression of a transgene (bioluminescent protein). In the remaining work for Aim 2, we will load these cells into biomaterial niches and implant them in vivo to monitor for expression of specific cytokines involved in experimental autoimmune encephalomyelitis (EAE – mouse model of MS). In Aim 3 we 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.

多发性硬化症（MS）是一种脱髓鞘的自身免疫性疾病，很难在临床上处理，因为 它的特征是无法预测的缓解和缓解时期。如果可以适当地 受到监控，可能药物可能会干预以防止损害，降低救济率和整体 进展。理想情况下，有可能反复进行中枢神经系统进行监测，但这也是 具有挑战性/病态具有实用性。在我工作的K99阶段，我们开发了一种利用组织的方法 工程原则以开发体内免疫利基（in），以获得与物理相关的收获 免疫种群。此外，我们开发了基于合成生物学的生物传感器 响应特定配体的可检测信号。在R00阶段，我建议在这个领域继续工作， 通过在体内测试生物传感器，工程专门富集了适应性的致病种群 免疫细胞，并利用组合生物传感器并设计用于监测细胞因子的表达 在体内抗原表现过程中。在AIM 2（正在进行中）我们开发了三个不同的工程接收器 结合配体二聚体并解放工程转录因子（TF）的系统。这个TF流量 到核并诱导转化（生物发光蛋白）的表达。在AIM 2的其余工作中， 我们将将这些细胞加载到生物材料壁ni中，并将它们植入体内以监测特定的表达 参与实验性自身免疫性脑脊髓炎的细胞因子（EAE - MS小鼠模型）。在目标3中我们 通过将抗原掺入中 脚手架。本节将创建一个反映自适应免疫的非侵入性传感器和多元签名 替代物和利用天生和自适应INS内的变化，以调查机理问题 关于MS发展中的先天自适应串扰。总之这些研究将创建工程 免疫利基和非侵入性传感器能够创建增强的诊断，预后学， 治疗监测器和没有安乐死的纵向免疫学研究。