Design of Fe2+ and H2O2 Induced Proximity Functionalized Imaging Probes for the Control of Cellular Functions

用于控制细胞功能的 Fe2 和 H2O2 诱导接近功能化成像探针的设计

• 批准号: 10388365
• 负责人: WEI WANG
• 金额: $ 28.72万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388365
• 关键词: Abscisic Acid; Address; Biological; Biological Process; Biomedical Research; Biotechnology; Brain-Derived Neurotrophic Factor; Buffers; Cell Death; Cell Therapy; Cell physiology; Cells; Chemicals; Complex; Cues; Detection; Disease; Engineering; Environment; Event; Fluorescence Microscopy; Functional Imaging; Future; Genes; Genetic; Gibberellins; High Pressure Liquid Chromatography; Hydrogen Peroxide; Immune response; Knowledge; Logic; Luciferases; Mediating; Mediator of activation protein; Methods; Microscopy; Molecular Biology; Mutation; Nature; Neurodegenerative Disorders; Neurons; Noise; Oxidative Stress; Pathway interactions; Production; Proteins; Reporting; Research; Research Proposals; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Specificity; Stimulus; Technology; Testing; Therapeutic; Toxic effect; Translations; biological systems; design; gene therapy; imaging probe; improved; innovation; new technology; novel; plasmid DNA; programs; protective effect; sensor; side effect; spatiotemporal; stability testing; synthetic biology; theranostics; therapeutic protein; tool

Project Summary Gene/cell therapies finally come of age thanks to the fundamental advances made by innovative and improved biotechnologies. Nonetheless, many challenges particularly toxicity and undesired/uncontrolled immune response remain. This research proposal addresses these concerns and represents a critical first step toward developing novel, more effective cell/gene therapy. Toward this end, we propose a novel synthetic biology technology termed “Environment Stimuli-Induced Proximity (ESIP)” to spatiotemporally manipulate cellular functions. The new strategy can overcome the difficulty of the established chemically induced proximity (CIP) method to mediate the translation of endogenous cellular signals into tailored cellular functions with spatiotemporal precision. To demonstrate the feasibility, we propose to develop fluorescent and chemiluminescent Fe(II) and H2O2 responsive ESIP chemical inducers because Fe(II) and H2O2 are important signal molecules, which are associated with numerous biological functions and diseases, and gibberellin (GA) and abscisic acid (ABA) are established chemical inducers with low toxicity. Specifically, we will design, synthesize, test and optimize Fe2+ and H2O2-responsive fluorescent and chemiluminescent ESIP inducers (Specific Aims 1-2) and test them in cells and construct ESIP-mediated “AND” Boolean logic gates to control the conditional production of AD therapeutic proteins (Specific Aim 3). These studies will prove that these `smart' theranostic probes possess the ability to sense endogenous Fe(II) and H2O2 specifically, and the ability to trigger the release of original bioactive chemical inducers GA and ABA, which then induce downstream biological functions such as luciferase expression and the production of neuron protective BDNF proteins. The technology will ultimately be transformed into entirely new cell/gene therapies for disease treatment with significantly reduced side effects. It is expected that this powerful and general strategy can be integrated with a variety of existing synthetic biology molecular parts and tools to build new cellular genetic and signaling circuitries to generate new functions as toolbox for biomedical research and as therapeutics for various disease treatment.

项目摘要 基因/细胞疗法终于成熟了，这要归功于创新和 改进的生物技术。尽管如此，许多挑战，特别是毒性和不希望的/不受控制的 免疫反应仍然存在。这项研究提案解决了这些问题，是关键的第一步 开发新的、更有效的细胞/基因疗法。为此，我们提出了一种新的合成 被称为“环境刺激诱导邻近（ESIP）”的生物技术来时空操纵 细胞功能。新策略可以克服已建立的化学诱导邻近的困难 (CIP)介导内源性细胞信号翻译成定制细胞功能的方法， 时空精确度。为了证明可行性，我们建议开发荧光和 荧光Fe（II）和H2 O2响应的ESIP化学诱导剂，因为Fe（II）和H2 O2是重要的 与多种生物学功能和疾病相关的信号分子，以及赤霉素（GA） 和脱落酸（阿坝）是公认的低毒化学诱导剂。具体来说，我们将设计， Fe ~（2+）和H_2O_2响应性荧光和荧光ESIP诱导剂合成、测试和优化 （具体目标1-2）并在细胞中测试它们并构建ESIP介导的“与”布尔逻辑门来控制 AD治疗性蛋白质的条件性产生（特异性目标3）。这些研究将证明，这些“聪明”的 治疗诊断探针具有特异性地感测内源性Fe（II）和H2 O2的能力，以及触发 原始生物活性化学诱导物GA和阿坝的释放，其然后诱导下游生物活性物质的释放， 功能如荧光素酶表达和神经元保护性BDNF蛋白的产生。技术 最终将转化为全新的细胞/基因疗法，用于疾病治疗， 减少副作用。预计这一强有力的通用战略可以与各种 现有的合成生物学分子部件和工具，以建立新的细胞遗传和信号电路， 作为生物医学研究的工具箱和各种疾病治疗的治疗剂产生新的功能。

项目成果

Senolysis Enabled by Senescent Cell-Sensitive Bioorthogonal Tetrazine Ligation.

通过衰老细胞敏感的生物正交四嗪连接实现衰老分解。

• DOI: 10.1002/anie.202315425
• 发表时间: 2024
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Chang,Mengyang;Dong,Yue;Xu,Hang;Cruickshank-Taylor,AlexisB;Kozora,JacobS;Behpour,Baran;Wang,Wei
• 通讯作者: Wang,Wei

A theranostic abscisic acid-based molecular glue.

• DOI: 10.1039/d2sc06995d
• 发表时间: 2023-03-22
• 期刊: Chemical science
• 影响因子: 8.4

Building bioorthogonal click-release capable artificial receptors on cancer cell surface for imaging, drug targeting and delivery.

• DOI: 10.1016/j.apsb.2022.12.018
• 发表时间: 2023-06
• 期刊: ACTA PHARMACEUTICA SINICA B
• 影响因子: 14.5
• 作者: Chen, Jing;Ji, Peng;Gnawali, Giri;Chang, Mengyang;Gao, Feng;Xu, Hang;Wang, Wei
• 通讯作者: Wang, Wei

MDM2-BCL-XL PROTACs enable degradation of BCL-XL and stabilization of p53.

• DOI: 10.15212/amm-2022-0022
• 发表时间: 2022-07-21
• 期刊: Acta materia medica
• 作者: Chang, Mengyang;Gao, Feng;Wang, Wei
• 通讯作者: Wang, Wei