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，临床上很难处理，因为 它的特点是病情缓解和复发的时期不可预测。如果这种疾病能够足够地 在监测下，药物可能会干预以防止损害，降低复发率和总体 进步。理想情况下，可以重复对中枢神经系统进行活组织检查，但这也太 具有挑战性/病态地想要有效用。在我工作的K99阶段，我们开发了一种利用组织的方法 在体内开发免疫小生境(IN)以实现生理相关的收获的工程原理 免疫种群。此外，我们开发了基于合成生物学的生物传感器，这种传感器可以通过光学方式产生 对特定配体作出反应的可检测信号。在R00阶段，我建议继续我在这个领域的工作， 通过在体内测试生物传感器，工程INS专门丰富适应性致病种群 免疫细胞，并利用组合生物传感器和工程化IN来监测细胞因子的表达 在体内呈现抗原的过程中。在目标2(正在进行中)中，我们开发了三种不同的工程受体 与配体结合后发生二聚化并释放出工程转录因子(TF)的系统。这个TF流量 并诱导转基因(生物发光蛋白)的表达。在目标2的剩余工作中， 我们将把这些细胞装载到生物材料的壁龛中，并将它们植入体内，以监测特定基因的表达 细胞因子参与实验性自身免疫性脑脊髓炎(EAE-MS小鼠模型)。在《目标3》中我们 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。本部分将创建反映自适应免疫的非侵入性传感器和多元特征 代理内部的变化，并利用先天和适应性IN来研究机械性问题 关于先天自适应串扰在多发性硬化症发展中的作用 免疫利基和非侵入性传感器，使增强的诊断、预后、 没有安乐死的治疗监测和纵向免疫学研究。