Non-Invasive and Non-Viral Sono-Optogenetics

非侵入性和非病毒声光遗传学

• 批准号: 10501831
• 负责人: Huiliang Wang
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501831
• 关键词: Address; Animals; Area; Award; Blood; Brain; Cations; Cells; Chemicals; Color; Craniotomy; Diffuse; Disease; Economics; Endosomes; Extracellular Space; Focused Ultrasound; Gene Expression; Genes; Goals; Guidelines; Heart; Hydrogen Bonding; Immune response; Light; Liver; Muscle Cells; Names; Polymers; Proteins; Research; Research Personnel; Safety; Technology; Time; Tissues; United States National Institutes of Health; Viral; Work; cell injury; design; implantation; improved; nanomaterials; nanoparticle; neuroregulation; non-viral gene delivery; optical fiber; optogenetics; plasmid DNA; protein protein interaction; spatiotemporal; ultrasound; uptake

Project Abstract Over the past decade, optogenetics has increasingly become an important technology for spatiotemporal control of neural activity, cardio functions, muscle cell activity, protein-protein interaction, and disease applications, through the genetically encoded light-activated proteins. However, there are still two major challenges of this technology: 1.the delivery of light to into deep body areas such as brain or heart generally requires the optical fiber implantation which could result in damage of cells and tissue. 2. Gene expression requires viral transduction, which suffer from a number of limitations such as the host immune response, the stability expressed proteins over time, the limitations on maximum gene size and the lack of economic scalability for manufacture. To address the first challenge, we recently developed a technology named ‘sono-optogenetics’ to convert focused ultrasound (FUS) to light for non-invasive optogenetics. The nanoparticles are injected into the circulating blood so that neither craniotomy nor intracranial implantation is required for achieving optogenetics. However, these inorganic nanoparticles are generally difficult to be modified to emit different colors of light for multiplex optogenetic control and are not biodegradable after accumulating in the animal livers after use, causing long-term safety concerns. Therefore, the goal of this proposal and the focus of my research lab, is to tackle the remaining challenges for optogenetics through designing organic nanomaterials, including hydrogen-bonded organic frameworks nanoparticles, chemical assembly of DNA plasmids and cationic polymer delivery agents. Specifically, we are planning to 1) design biodegradable nanoparticles to convert ultrasound to light for multi-colored sono- optogenetics. 2) improve the delivery of plasmid DNAs through nucleopore through covalent chemical assembly strategies and 3) design advanced cationic polymers for improving endosome escape, cellular uptake and diffusivity through extracellular space in non-viral gene delivery. The work will also enhance our understanding the transport and interaction of organic nanoparticles in cells. As a result, I believe that the proposed works is well suited for the NIH R35 Maximizing Investigators’ Research Award.

项目摘要 过去十年，光遗传学日益成为时空控制的重要技术 神经活动、心脏功能、肌肉细胞活动、蛋白质-蛋白质相互作用和疾病应用， 通过基因编码的光激活蛋白。然而，这一举措仍面临两大挑战 技术： 1.将光传输到大脑或心脏等身体深层区域通常需要光学 纤维植入可能会导致细胞和组织损伤。 2.基因表达需要病毒转导， 其受到许多限制，例如宿主免疫反应、表达蛋白的稳定性 随着时间的推移，最大基因大小的限制以及制造的经济可扩展性的缺乏。致地址 第一个挑战是，我们最近开发了一种名为“声光遗传学”的技术来转换聚焦超声波 （FUS）到光进行非侵入性光遗传学。将纳米粒子注入循环血液中，以便 实现光遗传学不需要开颅手术或颅内植入。然而，这些无机物 纳米粒子通常难以被修饰以发射不同颜色的光以进行多重光遗传学控制 使用后在动物肝脏中积累后不可生物降解，引起长期的安全问题。 因此，该提案的目标和我的研究实验室的重点是解决剩余的挑战 通过设计有机纳米材料（包括氢键有机框架）进行光遗传学 纳米颗粒、DNA 质粒的化学组装和阳离子聚合物递送剂。具体来说，我们是 计划1）设计可生物降解的纳米颗粒，将超声波转换为光，以产生多色声波 光遗传学。 2) 通过共价化学组装改善质粒 DNA 通过核孔的传递 策略和 3) 设计先进的阳离子聚合物以改善内体逃逸、细胞摄取和 非病毒基因传递中通过细胞外空间的扩散性。这项工作也将增进我们的理解 有机纳米粒子在细胞中的运输和相互作用。因此，我认为拟议的作品是 非常适合获得 NIH R35 最大化研究者研究奖。