CAREER: The nanoscale dynamics of molecular sorting, membrane curvature, and endocytosis

职业：分子分选、膜曲率和内吞作用的纳米级动力学

• 批准号: 1652316
• 负责人: Christopher Kelly
• 金额: $ 50万
• 依托单位: Wayne State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1652316&HistoricalAwards=false
• 关键词: CAREER; nanoscale; dynamics; molecular; sorting

Nontechnical: This CAREER award by the Biomaterials program in the Division of Materials Research to Wayne State University is to support the research and educational efforts focused on nanoscale membrane processes. Biological membranes are complex and dynamic two-dimensional fluid structures that are responsible for binding, internalizing and transporting materials. Membrane processes are inadequately understood at present, and this lack of in depth knowledge is limiting biomedical advancement in diverse neurological, immunological, and metabolic conditions. Developing an understanding and resolving the underlying membrane processes would guide the development of novel membrane like materials for potential applications in battery, long term food preservation, liposome-based cargo (drug, DNA, RNA, etc.) delivery without endosome uptake among others. Further, the educational impact of this award will be in the training of a technically skilled workforce, and these efforts will be coordinated with the Michigan Science Center. This award will support the development and implementation of a hands-on educational program to address the Next-Generation Science Standards, and these activities are expected to impact a large number of local K-12 students annually. Technical: This CAREER award supports the development and use of nanoscopic optical methods to measure the molecular-scale causes and effects of membrane curvature and functions. Using polarized localization microscopy, a super-resolution optical technique developed by the PI that is capable of simultaneously measuring dynamic membrane curvature and molecular organization, the following studies will be carried out to: 1) quantify the interplay of nanoscale membrane curvature with lipid phase separation; 2) resolve the contributions of curvature sensing and lipid phase preference on the sorting of phosphoinositide phosphates; and 3) observe the nanoscale membrane organization surrounding clathrin- and caveolin-independent endocytosis. Membrane functions require an understanding of many components of membranes including lateral composition variation, local variations in membrane physical properties such as thickness, bending, rigidity, tension, curvature, and fluidity. By understanding the interdependence of fundamental physical principles that regulate membrane functions, this project would create a foundational understanding in developing novel biomimetic membranes and applications in scientific and technological fields. This research will also address previously untestable hypotheses regarding the mechanisms initiating receptor-independent endocytosis. The results from these studies will guide both basic scientists to understand mechanisms in nano-biology, and applied scientists aiming to better control membrane processes and functions including the interplay between membrane properties that are critical for high-throughput membranes, liposome-based drug targeting, and nanoliter chemistry applications. Additionally, this award will support the development of nanoscopic methods, improved understandings of nanoscale biology, and dissemination of these advancements through the training of students. The proposed educational and training activities in coordination with the Michigan Science Center are expected to impact a large number of K-12 students in preparing them for higher education in STEM and a technically skilled workforce. The economy and society will benefit from the proposed training of a high-tech workforce, improved scientific literacy, new biological insights, and technological advances made possible by this award.

非技术性：该职业奖由材料研究部的生物材料项目授予韦恩州立大学，旨在支持专注于纳米级膜工艺的研究和教育工作。生物膜是复杂的动态二维流体结构，负责结合，内化和运输材料。目前对膜过程的了解还不够，这种缺乏深入了解的情况限制了生物医学在各种神经、免疫和代谢条件下的进步。理解和解决潜在的膜过程将指导新型膜状材料的开发，用于电池、长期食品保存、基于脂质体的货物（药物、DNA、RNA等）等的潜在应用。没有内体摄取的递送等。此外，该奖项的教育影响将在技术熟练的劳动力的培训，这些努力将与密歇根科学中心协调。该奖项将支持开发和实施实践教育计划，以解决下一代科学标准，这些活动预计将每年影响大量当地K-12学生。技术支持：该CAREER奖支持纳米光学方法的开发和使用，以测量膜曲率和功能的分子尺度原因和影响。利用偏振定位显微镜，一种由PI开发的能够同时测量动态膜曲率和分子组织的超分辨率光学技术，将进行以下研究：1）量化纳米级膜曲率与脂质相分离的相互作用; 2）解决曲率传感和脂质相偏好对磷酸肌醇磷酸分选的贡献;和3）观察围绕网格蛋白和小窝蛋白非依赖性内吞作用的纳米级膜组织。膜功能需要了解膜的许多组成部分，包括横向组成变化，膜物理性质的局部变化，如厚度，弯曲，刚度，张力，曲率和流动性。通过了解调节膜功能的基本物理原理的相互依赖性，该项目将在开发新型仿生膜和科学技术领域的应用方面建立基础性理解。这项研究还将解决以前无法验证的假设，启动受体非依赖性内吞作用的机制。这些研究的结果将指导基础科学家了解纳米生物学的机制，以及旨在更好地控制膜过程和功能的应用科学家，包括对高通量膜，基于脂质体的药物靶向和纳升化学应用至关重要的膜特性之间的相互作用。此外，该奖项将支持纳米方法的发展，提高对纳米生物学的理解，并通过对学生的培训传播这些进步。与密歇根科学中心协调的拟议教育和培训活动预计将影响大量K-12学生，为他们接受STEM高等教育和技术熟练的劳动力做好准备。经济和社会将受益于高科技劳动力的拟议培训，提高科学素养，新的生物学见解以及该奖项所带来的技术进步。

项目成果

Nanoscale Membrane Budding Induced by CTxB and Detected via Polarized Localization Microscopy

• DOI: 10.1016/j.bpj.2017.08.031
• 发表时间: 2017-10-17
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Kabbani, Abir M.;Kelly, Christopher V.
• 通讯作者: Kelly, Christopher V.

Membrane asymmetry enhances nanotube formation and limits pore resealing after electroporation

膜的不对称性增强了纳米管的形成并限制了电穿孔后孔的重新密封

• DOI: 10.1016/j.bpj.2022.07.037
• 发表时间: 2022
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Gandhi, Sonali A.;Kelly, Christopher V.
• 通讯作者: Kelly, Christopher V.

Nanoscale membrane curvature sorts lipid phases and alters lipid diffusion

纳米级膜曲率对脂质相进行分类并改变脂质扩散

• DOI: 10.1016/j.bpj.2023.01.001
• 发表时间: 2023
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Woodward, Xinxin;Javanainen, Matti;Fábián, Balázs;Kelly, Christopher V.
• 通讯作者: Kelly, Christopher V.

Anisotropic diffusion of membrane proteins at experimental timescales

实验时间尺度下膜蛋白的各向异性扩散

• DOI: 10.1063/5.0054973
• 发表时间: 2021
• 期刊: The Journal of Chemical Physics
• 作者: Javanainen, Matti;Martinez-Seara, Hector;Kelly, Christopher V.;Jungwirth, Pavel;Fábián, Balázs
• 通讯作者: Fábián, Balázs

The Detection of Nanoscale Membrane Bending with Polarized Localization Microscopy

• DOI: 10.1016/j.bpj.2017.07.034
• 发表时间: 2017-10-17
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Kabbani, Abir M.;Kelly, Christopher V.
• 通讯作者: Kelly, Christopher V.