Administrative Supplement for Equipment for Integrating Real-Time Multi-System Cytokine Signaling in Chronic Disease

慢性病实时多系统细胞因子信号转导设备集成管理补充

• 批准号: 10797254
• 负责人: Ryan Martin Williams
• 金额: $ 24.96万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797254
• 关键词: Acute; Administrative Supplement; Animals; Autoimmune Diseases; Award; Blood; Carbon; Cardiovascular Diseases; Cells; Chronic; Chronic Disease; Chronic Kidney Failure; Chronic Phase; Communicable Diseases; Coupled; Cytokine Signaling; Data; Detection; Development; Disease; Disease Progression; Disease model; Encapsulated; Ensure; Equipment; Evaluation Research; Exhibits; Fluorescence; Future; Hydrogels; Image; Imaging Techniques; Immune response; Immunoassay; In Situ; Inflammation; Inflammatory; Inflammatory Response; Injectable; Injections; Kinetics; Laboratories; Light; Link; Location; Malignant Neoplasms; Measurement; Measures; Microscope; Modeling; Mus; Musculoskeletal Diseases; Neurodegenerative Disorders; Organ; Parents; Pathogenesis; Photons; Process; Productivity; Proteins; Research; Research Methodology; Rodent Model; Role; Scientist; Signal Transduction; Specificity; Stains; System; Time; Time Study; Tissues; Work; cytokine; design; end stage disease; fluorescence microscope; implantation; in vivo; infrared microscopy; insight; instrument; manufacture; minimally invasive; molecular imaging; nanosensors; rapid detection; sensor; systemic inflammatory response; technology validation; transcriptome sequencing; whole animal imaging

Project Summary/Abstract of the Parent Award Over the next five years, my laboratory aims to study time-resolved systemic inflammation across multiple chronic diseases. Though pro-inflammatory cytokine signaling is common amongst chronic diseases, it is unclear what cytokines are active at various timepoints throughout disease initiation and progression. It is also unclear what cytokines are functional in the inflection from acute to chronic-phase inflammatory signaling. Current methods of research evaluation are not amenable to rapid kinetics (enzymatic immunoassays) or quantitative multiplexing (molecular imaging techniques). We plan to use a fluorescent carbon nanosensor-based platform I have previously developed, modified to rapidly detect pro-inflammatory cytokines in a multiplexed manner. The multiplexed cytokine nanosensor will be encapsulated within an injectable hydrogel matrix for minimally-invasive implantation and rapid measurement. We will use this sensor platform to create a cytokine signal detection network for both circulating and in situ cytokine signals in rodent models of chronic diseases. The nanosensor network will initially be validated in healthy mice using exogenous cytokine injection. We will ensure the sensor detects multiple cytokines simultaneously, at disease-relevant concentrations, is functional for months, and exhibits no specificity issues. The encapsulating hydrogel matrix will be designed to allow passage of proteins but retention of the sensor based on size, and will undergo minimal biofouling. Following technology validation, we will use the nanosensor network to measure local and circulating cytokine levels in at least eight models of chronic disease, including: cardiovascular disease, cancer, neurodegenerative disease, and autoimmune disease. Future work will be extended to infectious disease, chronic renal disease, musculoskeletal disease, and others. In each disease model, we will couple traditional assessments of inflammation and immune response, as evaluated by weekly blood draws coupled with enzymatic immunoassays. Local inflammation will also be evaluated at the time of sacrifice via single-cell transcriptomic sequencing and immunohistochemical staining. Kinetic cytokine measurements will be obtained via the nanosensor network, deployed in at least 7 locations in each animal, 2 local and 2 systemic, via hydrogel injection. Each will be measured daily for kinetic cytokine quantification prior to and immediately after disease initiation, during chronic progression, and during end-stage disease. Sensor measurement will be performed via whole-animal imaging and simple 3-second light excitation non-invasively from outside the animal. These sensors will provide real-time, long-term quantification of cytokine concentrations throughout disease progression. We expect to understand kinetic cytokine changes in the inflection from acute to chronic inflammatory responses and the pro-inflammatory contribution of multiple organs during disease development. We will investigate pro-inflammatory cytokine signatures for each disease at specific times in its development, providing scientists studying each field difficult-to-obtain dynamic data and further insight into the pathogenesis of chronic disease.

项目总结/家长奖摘要 在接下来的五年中，我的实验室的目标是研究跨多个时间分辨的系统性炎症 慢性疾病。尽管促炎细胞因子信号传导在慢性疾病中很常见，但尚不清楚 在疾病发生和进展的各个时间点哪些细胞因子是活跃的。也不清楚 哪些细胞因子在从急性期到慢性期炎症信号传导的转变中发挥作用。当前的 研究评估方法不适合快速动力学（酶免疫分析）或定量 多重分析（分子成像技术）。我们计划使用基于荧光碳纳米传感器的平台 I 先前已开发并修改为以多重方式快速检测促炎细胞因子。这 多重细胞因子纳米传感器将封装在可注射水凝胶基质中，用于微创 植入和快速测量。我们将使用这个传感器平台来创建细胞因子信号检测 慢性疾病啮齿动物模型中循环和原位细胞因子信号网络。纳米传感器 该网络最初将通过注射外源细胞因子在健康小鼠中进行验证。我们将确保传感器 同时检测疾病相关浓度的多种细胞因子，可以持续数月发挥作用，并且 不存在特异性问题。封装水凝胶基质将被设计成允许蛋白质通过 但传感器的保留取决于尺寸，并且将遭受最小的生物污染。经过技术验证， 我们将使用纳米传感器网络来测量至少八个模型的局部和循环细胞因子水平 慢性疾病，包括：心血管疾病、癌症、神经退行性疾病和自身免疫性疾病 疾病。未来的工作将扩展到传染病、慢性肾病、肌肉骨骼疾病和 其他的。在每种疾病模型中，我们将结合炎症和免疫反应的传统评估， 通过每周抽血结合酶免疫测定进行评估。局部也会有炎症 在处死时通过单细胞转录组测序和免疫组织化学染色进行评估。 动力学细胞因子测量将通过纳米传感器网络获得，该网络部署在至少 7 个地点 每只动物，2只局部和2只全身，通过水凝胶注射。每天测量每个细胞因子的动态细胞因子 在疾病发生之前和之后立即、慢性进展期间和末期进行量化 疾病。传感器测量将通过整个动物成像和简单的 3 秒光激发来进行 来自动物体外的非侵入性。这些传感器将提供细胞因子的实时、长期定量 整个疾病进展过程中的浓度。我们期望了解细胞因子的动力学变化 从急性到慢性炎症反应的转变以及多个器官的促炎作用 疾病发展过程中。我们将研究每种疾病的促炎细胞因子特征 其发展的特定时期，为研究各个领域的科学家提供难以获得的动态数据和 进一步深入了解慢性病的发病机制。