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

多发性硬化症（MS）是一种脱髓鞘自身免疫性疾病，临床上难以管理，因为 其特征在于不可预测的缓解和复发期。如果这种疾病能够充分 监测，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，有可能反复对CNS进行活检以进行监测，但这太 具有挑战性/病态的实用性。在K99阶段，我们开发了一种方法， 工程原理，以在体内开发免疫生态位（IN），从而能够收获生理学相关的 免疫人群。此外，我们开发了基于合成生物学的生物传感器， 响应于特定配体的可检测信号。在R 00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IN，特别是丰富适应性病原体群体， 免疫细胞，并利用生物传感器和工程化IN的组合来监测细胞因子的表达 在体内抗原呈递期间。在Aim 2（正在进行中）中，我们开发了三种不同的工程受体， 在结合配体时二聚化并释放工程化转录因子（TF）的系统。这个TF交通 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入生物材料龛中，并将它们植入体内，以监测特定的 参与实验性自身免疫性脑脊髓炎（EAE -MS小鼠模型）的细胞因子。在目标3中， 将通过将抗原掺入CNS中的免疫细胞内， 脚手架本节将创建反映适应性免疫的非侵入性传感器和多变量特征 代理人内部的变化，并利用先天和适应性IN来研究机械问题 关于MS发展中的先天自适应串扰。综合这些研究， 免疫学小生境和非侵入性传感器，使增强诊断，免疫学， 治疗监测器和纵向免疫学研究而不实施安乐死。

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.