Sonogenetics 2.0

声遗传学2.0

• 批准号: 10734960
• 负责人: Hong Chen
• 金额: $ 64.14万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734960
• 关键词: 3D Print; Acoustics; Address; Animals; Area; Benchmarking; Biological; Biomedical Engineering; Brain; Brain Diseases; Brain region; Cell membrane; Cell physiology; Collaborations; Communities; Corpus striatum structure; Data; Dependovirus; Development; Device Designs; Devices; Dopamine D1 Receptor; Drug Delivery Systems; Engineering; Exhibits; Focused Ultrasound; Gene Delivery; Genetic; Genetic Engineering; Goals; Human; Injections; Intranasal Administration; Investigation; Ion Channel; Ions; Laboratories; Light; Location; Mediating; Microbubbles; Modality; Molecular Probes; Motor; Mus; Mutagenesis; Neurons; Neurosciences; Neurosciences Research; Operative Surgical Procedures; Penetration; Performance; Population; Process; Property; Public Health; Publishing; Research; Research Personnel; Research Project Grants; Resolution; Rodent; Safety; Serotyping; Sonication; Structure; TRPV1 gene; Techniques; Technology; Tissues; Transducers; Translating; Ultrasonic Therapy; Ultrasonic Transducer; Ultrasonics; Validation; Variant; Viral Vector; adeno-associated viral vector; cell type; efficacy evaluation; free behavior; genetic manipulation; improved; infancy; innovation; lens; millisecond; mind control; motor control; multidisciplinary; mutant; neural; neural circuit; neuroregulation; next generation; optogenetics; response; technology development; tool; translational potential; ultrasound

PROJECT SUMMARY/ABSTRACT Achieving noninvasive, cell-type-specific, and spatially precise neuromodulation remains to be a major challenge in the development of neuromodulation technologies. The objective of this project is to develop Sonogenetics 2.0, the next-generation sonogenetic technique for cell-type-specific, spatially precise neuromodulation in the whole brain of freely behaving animals without intracranial surgery. Sonogenetics 2.0 employs low-intensity focused ultrasound (FUS) combined with microbubbles to deliver intranasally administered adeno-associated viruses (AAVs) to the FUS-targeted brain region with minimal systemic exposure. It then utilizes FUS sonication to remotely activate the expressed ultrasound-sensitive ion channels encoded by the AAVs and thereby controls the activity of AAV-transduced neurons. Sonogenetics 2.0 addresses three critical barriers to developing sonogenetics: the lacks molecular probes with optimized ultrasound sensitivity (Aim 1), requires surgical injection of viral vectors to express the probes (Aim 2), and has a low spatial resolution in delivering ultrasound in the mouse brain (Aim 3). Sonogenetics 2.0 will be independently validated by neuroscience laboratories and benchmarked with optogenetics (Aim 4). The proposed Sonogenetics 2.0 is significant because technological breakthroughs are urgently needed to fulfill the great potential of sonogenetics. Sonogenetics 2.0 provides a complementary tool to existing neuromodulation techniques with the potential to be translated to large animals and humans. A multidisciplinary team with combined expertise in ultrasound device design, ion channel engineering, neuromodulation, and neuroscience is well suited to this project. This project is innovative because Sonogenetics 2.0 is the first-in-class ultrasound tool for completely noninvasive and cell-type-specific neuromodulation by combining noninvasive genetic construct delivery with noninvasive activation of transduced neurons. The proposed research is expected to have a sustained, powerful impact in the research field of sonogenetics and provide the neuroscience community with a transformative tool that can be widely used to advance our current capabilities in investigating cell-type-specific processes in intact mammalian brains.

项目摘要/摘要 实现无创，细胞型特异性和空间精确的神经调节仍然是主要的 神经调节技术开发的挑战。该项目的目的是开发 Sonogentics 2.0，一种用于细胞类型的，在空间上精确的下一代声遗传学技术 在没有颅内手术的情况下自由表现动物的整个大脑中的神经调节。 Sonogentics 2.0 采用低强度聚焦超声（FUS）与微泡相结合以提供鼻内给药 腺体相关病毒（AAVS），可至关重要的脑区域，具有最小的全身性暴露。然后 利用FUS超声处理来远程激活由 AAVS，从而控制AAV转导神经元的活性。 Sonogentics 2.0解决了三个关键 发展性声遗传学的障碍：缺乏具有优化超声灵敏度的分子探针（AIM 1）， 需要手术注射病毒向量才能表达探针（AIM 2），并且空间分辨率低。 在小鼠大脑中传递超声（AIM 3）。 Sonogenetics 2.0将由 神经科学实验室，并通过光遗传学测试（AIM 4）。拟议的Sonogenetics 2.0是 意义重大，因为迫切需要技术突破来实现 发音学。 Sonogenetics 2.0提供了与现有神经调节技术的补充工具 可能被翻译成大型动物和人类。一个具有联合专业知识的多学科团队 超声设备设计，离子通道工程，神经调节和神经科学非常适合此 项目。该项目具有创新性，因为Sonogenotics 2.0是完全的一流超声工具 通过将非侵入性遗传构建体递送与非侵入性和细胞型特异性神经调节 转导神经元的无创激活。拟议的研究预计将具有持续，有力的 在声遗传学研究领域的影响，并为神经科学社区提供变革性的工具 可以广泛用于提高我们当前研究细胞类型特定过程的能力 哺乳动物的大脑。