Collaborative Research: NSF-ANR MCB/PHY: Probing Heterogeneity of Biological Systems by Force Spectroscopy

生物分子可以以多种不同的状态存在，这影响了它们在健康和疾病背景下的功能。我们目前用来研究这些分子的许多工具都是测量不同状态的平均性质，隐藏了潜在的异质性。该奖项将通过实验和理论的结合帮助破译这种异质性的本质，包括：1)高速原子力光谱学的新方法，它对单个分子(例如蛋白质、脂类或结合分子的复合体)施加快速增加的力，以解开或打破它们；2)机器学习和其他数据分析技术，可以从实验结果中提取信息，以表征分子的原始状态及其动力学；3)分析活细胞中分子的异质性，特别是将细胞结合在一起的黏附复合体。为了实现这一目标，该项目汇集了一个由生物物理学家和工程师组成的多学科联盟。该项目的广泛影响将导致开发下一代原子力显微镜工具，并可能应用于其他纳米技术平台，如光镊子。该理论和数据分析方法将普遍适用于任何生物系统，以及软物质和材料科学。预期的结果将与各种与健康相关的生物过程相关，从感染过程中的免疫识别到许多神经疾病中存在的涉及蛋白质聚集的病理。在教育方面，该项目将通过实习、暑期学校和接触更广泛社区的机会培养年轻研究人员的科学形成。美国/法国的这个合作项目得到了美国国家科学基金会(NSF)和法国国家科学基金会(ANR)的支持，其中NSF为美国调查人员提供资金，ANR为法国的合作伙伴提供资金。美国调查人员由数学和物理科学局的生命系统物理学计划和生物科学局的分子生物物理学计划/分子和细胞生物科学部共同资助。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Biological molecules can exist in a number of different states, which influences how they function in the context of health and disease. Many of the current tools that we use to study these molecules measure average properties across states, hiding the underlying heterogeneity. This award will help decipher the nature of this heterogeneity through a combination of experiments and theory, including: 1) new methods of high-speed atomic force spectroscopy, which applies a rapidly increasing force on individual molecules (for example proteins, lipids, or complexes of bound molecules) to unravel or break them; 2) machine learning and other data analysis techniques that can extract information from the experimental results, in order to characterize the original states of the molecules and their dynamics; 3) analyzing heterogeneity of molecules in living cells, particularly the adhesion complexes that bind cells together.To accomplish this, the project brings together a multidisciplinary consortium of biophysicists and engineers.Broader impacts of the project will lead to the development of next generation tools for atomic force microscopy, with potential applications to other nanotechnology platforms like optical tweezers. The theory and data analysis methods will be generally applicable to any biological system, as well as in soft matter and materials science. The expected results will be relevant for a variety of health-related biological processes, from immune recognition during infection to pathologies involving protein aggregation, present in many neurological disorders. In education, the project will foster the scientific formation of young researchers through internships, summer schools, and opportunities for outreach to the broader community. This collaborative US/France project is supported by the US National Science Foundation (NSF) and the French Agence Nationale de la Recherche (ANR), where NSF funds the US investigators and ANR funds the partners in France. The US investigators are jointly funded by the Physics of Living Systems program in the Directorate for Mathematical and Physical Sciences and the Molecular Biophysics program/Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.