Engineering mammalian gene activity sensor-actuator devices

工程哺乳动物基因活性传感器-执行器装置

• 批准号: 10211197
• 负责人: Laura Segatori
• 金额: $ 33.94万
• 依托单位: RICE UNIVERSITY
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211197
• 关键词: Acute; Amplifiers; Behavior; Biological Markers; Cell Therapy; Cell physiology; Cell surface; Cells; Chronic; Clinic; Clinical; Communicable Diseases; Complex; Cues; Custom; Data; Detection; Development; Devices; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Disease Marker; Dose; Dose-Limiting; Drug Controls; Drug Delivery Systems; Drug Regulations; Encapsulated; Engineered Gene; Engineering; Environment; Evolution; Gene Activation; Gene Amplification; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Transcription; Goals; Health; Human; Human Pathology; Hypoxia; Immunomodulators; Interleukin-2; Ligands; Link; Malignant Neoplasms; Mediating; Medical; Modern Medicine; Monitor; Output; Pathologic Processes; Patients; Performance; Pharmaceutical Preparations; Physiological; Physiological Processes; Process; Production; Property; Public Health; Quality of Care; Regulation; Research; Resistance; Resolution; Science; Series; Signal Transduction; Specificity; Stimulus; Synthetic Genes; System; Technology; Testing; Therapeutic; Time; Toxic effect; Translating; Treatment outcome; base; care outcomes; cell behavior; cellular engineering; conventional therapy; cytokine; design; drug production; effective therapy; extracellular; improved; innovation; monitoring device; non-Native; novel; prevent; programs; real time monitoring; receptor; response; sensor; side effect; systemic inflammatory response; systemic toxicity; technological innovation; technology development; therapeutically effective; therapy outcome; tool; treatment strategy; virtual

Engineering mammalian gene activity sensors-actuator devices Cellular devices that generate user-defined outputs in response to environmental cues hold unprecedented opportunities for modern medicine through the development of living designer systems that detect and correct human pathologies. These sensor-actuator devices are currently based on cell surface sensing capabilities, mostly achieved by rewiring native ligand-receptor interactions or evolving non-native receptors linked to signal transduction systems. The performance of receptor-based sensors depends ultimately on the signal transduction mechanism embedded in the receptor system, however, and may not accurately recapitulate the physiologic response to the biomarker input. Cellular physiological states are determined by complex mechanisms that integrate signals associated with different quantitative features of extracellular and intracellular cues and provide blueprints to regulate the levels, states, and dynamics of gene expression. Regulation of gene expression thus ultimately determines cell functionality during physiological and pathological processes and is constantly and dynamically modulated to respond to environmental as well as intracellular stimuli. We thus envisioned a novel class of cellular devices that actuate user-defined biomolecular programs in response to the detection of the device’s physiological state achieved through real-time monitoring of the activity of chromosomal genes. These gene activity sensor-actuator devices are based on innovative tools recently developed by our groups for designing orthogonal systems that (i) link output expression to chromosomal genes, thereby recapitulating complex mammalian regulatory processes with high fidelity, and (ii) amplify the signal output with high resolution of the input dynamics, thereby recapitulating dynamic behaviors with superior sensitivity. To generate robust sensor-actuator devices that translate detection of gene expression signatures into user-defined outputs, we will explore the design rules of sense-and-respond mechanisms for linking detection of gene activity to output production (Aim 1), translate gene activity into precisely modulated delays in output production (Aim 2), self- adjust output production in response to output-induced modulation of gene activity (Aim 3). This approach is expected to create a paradigm shift in the way we design cellular devices that sense and respond to the environment, as it will provide a strategy to engineer cells to sense virtually any cellular process associated with a transcriptional response, eliminating the need to rewire ligand-receptor interactions or evolve synthetic receptor-based devices. Results from this study will generate design rules of cellular devices that sense gene activity with high dynamic resolution, enabling the development of cell-based diagnostics and therapeutics for a diverse range of applications.

工程哺乳动物基因活性传感器-致动器装置 根据环境线索生成用户定义输出的蜂窝设备拥有前所未有的 现代医学的机会，通过发展活的设计师系统，检测和纠正人类 病理学这些传感器-致动器设备目前基于细胞表面传感能力，大多实现了 通过重新连接天然配体-受体相互作用或进化与信号转导系统相连的非天然受体。 基于受体的传感器的性能最终取决于嵌入在 然而，受体系统可能不能准确地再现对生物标记输入的生理反应。 细胞生理状态是由复杂的机制决定的，这些机制整合了与不同细胞相关的信号。 细胞外和细胞内线索的定量特征，并提供蓝图，以调节水平，状态， 基因表达的动力学因此，基因表达的调节最终决定了细胞功能， 生理和病理过程，并不断和动态地调节，以响应环境 以及细胞内刺激。因此，我们设想了一类新型的蜂窝设备， 生物分子程序响应于通过实时检测实现的设备的生理状态， 监测染色体基因的活性。这些基因活性传感器-致动器设备是基于创新的 我们的小组最近开发的工具，用于设计正交系统，（i）将输出表达式与 染色体基因，从而以高保真度再现复杂的哺乳动物调控过程，和（ii） 以输入动态的高分辨率放大信号输出，从而再现动态行为， 上级灵敏度。 为了产生强大的传感器-致动器设备，将基因表达特征的检测转化为用户定义的 输出，我们将探索设计规则的感觉和反应机制，将检测基因活性， 输出生产（目标1），将基因活性转化为精确调节的输出生产延迟（目标2），自我调节 响应输出诱导的基因活性调节来调整输出生产（目标3）。 这种方法有望在我们设计感知和响应的蜂窝设备的方式上创造一个范式转变。 环境，因为它将提供一种策略，工程细胞，以感知几乎任何细胞过程相关的 转录反应，消除了重新连接配体-受体相互作用或进化基于合成受体的 装置.这项研究的结果将产生细胞装置的设计规则，这些细胞装置以高灵敏度检测基因活性。 动态分辨率，使基于细胞的诊断和治疗的发展，为各种各样的 应用.