Integrating Real-Time Multi-System Cytokine Signaling in Chronic Disease

在慢性病中整合实时多系统细胞因子信号传导

基本信息

批准号：
10622769
负责人：
Ryan Martin Williams
金额：
$ 6.32万
依托单位：
CITY COLLEGE OF NEW YORK
依托单位国家：
美国
项目类别：
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/10622769
关键词：
Academia Acute Animals Autoimmune Diseases Award Biomedical Engineering Blood Carbon Cardiovascular Diseases Career Choice Cells Chronic Chronic Disease Chronic Kidney Failure Chronic Phase Cities Communicable Diseases Consult Coupled Cytokine Signaling Data Detection Development Disease Disease Progression Disease model Doctor of Philosophy Encapsulated Engineering Ensure Evaluation Research Exhibits Fellowship Funding Future Hydrogels Imaging Techniques Immune response Immunoassay In Situ Individual Industry Inflammation Inflammatory Inflammatory Response Injectable Injections Inosine Diphosphate Israel Kinetics Laboratories Life Cycle Stages Light Location Malignant Neoplasms Measurement Measures Mentors Mentorship Modeling Mus Musculoskeletal Diseases Neurodegenerative Disorders New York Organ Parents Participant Pathogenesis Proteins Research Methodology Research Personnel Rodent Model Role Science Scientist Signal Transduction Site Specificity Stains Students Testing Time Time Study Travel Wages Work base career development chronic inflammatory disease college cytokine design doctoral student end stage disease hypertensive implantation in vivo insight minimally invasive molecular imaging nanosensors parent project pre-doctoral programs research and development sensor single walled carbon nanotube symposium systemic inflammatory response technology validation training opportunity transcriptomics whole animal imaging

项目摘要

Project Summary/Abstract 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.

项目概要/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。