Sentinels: Living-Tissue for Doppler Detection of Emerging Microbial Threats

哨兵：用于多普勒检测新兴微生物威胁的活组织

• 批准号: 2200186
• 负责人: David Nolte
• 金额: $ 49.64万
• 依托单位: Purdue University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2200186&HistoricalAwards=false
• 关键词: Sentinels; Living; Tissue; Doppler; Detection

Antibiotic resistance may soon make common antibiotics ineffective, and there is a pressing need to find new-generation antimicrobial therapies. A novel approach to test antimicrobial drugs is to measure the effect of the drug on the microbes within living cells. Light reflected by small collections of living cells can sense when the cells are infected with microbes because the infection changes how the internal cellular machinery works. The use of natural intracellular motions in cell clusters that act as “sentinels” is an unprecedented new approach to detecting microbes. To further educational goals, the effect of cellular motion on reflected light will be easily demonstrated to high-school students using simple laser pointers and cell phone cameras.To improve the discovery of new antimicrobial compounds, a new physics-based optical screening technology will be developed to fill this need. Biodynamic Doppler profiling (BDP) performs Doppler spectroscopy of intracellular motions inside living tissue using low-coherence digital holography. It is a sensitive probe of the subtle changes of cellular dynamics caused by drugs or infections inside tissue. Biodynamic profiling has already been used to predict the response of cancer patients to chemotherapy by applying cancer drugs on living ex vivo biopsies. In this project the team will develop Doppler detection of bacterial infection of living-tissue sentinels. The premise of living-tissue sentinels is that the sentinel behavior is modified by early infection before the bacteria can be characterized directly themselves. In the proposed research, biodynamic profiling of microbial invasion will be extended along several lines by: 1) enhancing the sensitivity of the sentinels to detect lower-level bacterial infections; 2) assembling a library of sentinel response functions to microbial infection; 3) performing quantitative assays of antibiotic resistance; 4) demonstrating the first detection of viral infections of tissue sentinels, and 5) developing new deep-learning algorithms to classify pathogenicity and predict therapeutic efficacy. The outreach objective is to enlist undergraduates in the research experience, including under-represented groups in research, and developing hands-on intracellular motility imaging experiments for grades 7-12.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

抗生素耐药性可能很快使普通抗生素无效，迫切需要找到新一代抗菌疗法。测试抗微生物药物的一种新方法是测量药物对活细胞内微生物的影响。当细胞被微生物感染时，活细胞的小集合反射的光可以感知，因为感染改变了内部细胞机制的工作方式。利用细胞簇中的自然细胞内运动作为“哨兵”是一种前所未有的检测微生物的新方法。为了进一步实现教育目标，将使用简单的激光笔和手机摄像头向高中生轻松演示细胞运动对反射光的影响。为了促进新抗菌化合物的发现，将开发一种新的基于物理学的光学筛选技术来满足这一需求。 生物动力学多普勒分析（BDP）使用低相干数字全息术对活组织内的细胞内运动进行多普勒光谱分析。 它是由药物或组织内感染引起的细胞动力学微妙变化的敏感探针。 生物动力学分析已经被用于预测癌症患者对化疗的反应，方法是将癌症药物应用于活体离体活检。 在这个项目中，研究小组将开发多普勒检测活组织哨兵的细菌感染。 活组织哨兵的前提是，在细菌可以直接表征自身之前，哨兵行为被早期感染改变。 在拟议的研究中，微生物入侵的生物动力学分析将沿着沿着几条线扩展：1）提高哨兵的灵敏度以检测低水平的细菌感染; 2）组装哨兵对微生物感染的响应函数库; 3）进行抗生素耐药性的定量测定; 4）展示组织哨兵病毒感染的首次检测，5）开发新的深度学习算法来分类致病性和预测治疗效果。 推广的目标是招募本科生的研究经验，包括在研究中的代表性不足的群体，并开发动手细胞内运动成像实验的等级7-12.This奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。