CAREER: Physical and Evolutionary Constraints on Adaptive Immunity

复杂生命的一个显著特征是能够在威胁性微生物的入侵中生存下来--这些微生物种类繁多，而且不断变化。这依赖于拥有一个适应性免疫系统，从过去的遭遇中学习，以备将来保护。快速发展的数据采集技术已经揭示，自然发生的免疫反应在速度、效力和适应新挑战的能力方面是有限的，但其起源仍然知之甚少。该研究项目将调查在存在功能限制的情况下出现有效免疫反应背后的组织原则。通过解释原生微环境特有的特征，该项目将为细胞-细胞界面分子信息的物理提取如何塑造适应性免疫的进化驱动力提供预测框架，推进我们对活生物体中分子识别的理解。在该项目中，主要研究者（PI）将结合联合收割机理论和实验数据，解释和预测抗体库如何对相关抗原产生反应，为开发针对快速进化病原体的通用疫苗提供关键见解。拟议的研究活动将与教育和外联工作密切结合，为探索生命系统的物理学提供机会。一个核心要素是青年学生积极参与跨越多个传统领域的定量方法。通过与加州大学洛杉矶分校中心X科学项目的合作，PI将开发交互式在线学习模块，让服务不足的学区的高中学生和教师参与复杂系统的计算建模。为了在她的实验室提供第一手的研究经验，PI将继续通过加州大学洛杉矶分校的科学交流计划指导和招募代表性不足的大学生。为了给年轻科学家创造一种社区感，PI将在生物物理研讨会系列中心举办生物物理研究人员在其职业生涯的各个阶段发言。PI将通过在纯数学和应用数学研究所举办的研讨会以及在校园内探索你的宇宙活动中的展位来吸引公众。 实验技术在过去十年中的重大进展揭示了两个来源的限制-物理和进化-在不同复杂性的生物体中快速出现有效的免疫反应。但直到最近，我们仍然缺乏一个定量框架来确定这些限制的功能影响以及细胞可以控制和利用它们进行适应的程度。在这个项目中，PI将理论和计算建模与生物物理和诱变数据的分析相结合，以阐明免疫适应复杂抗原环境的限制和潜力。两个重点是（i）发展第一原理预测为什么免疫细胞使用主动过程从其他细胞表面物理提取抗原;（ii）从统计物理学扩展理论框架，以表征进化途径和免疫库在多样化和动态选择压力下的适应能力。理论预测将分别由探索物理和进化限制的合作小组进行测试。通过一个规模桥接模型框架的发展，这项研究将提供第一个演示的作用，细胞内的力产生在调节细胞群体的自然选择，奠定了基础，为全面了解分子识别的进化。在这个项目的过程中，PI将构建和验证新的措施来检测上位景观的丰富结构，并探索其进化后果，以弥合崎岖的健身景观进化动力学理论和实验之间的差距。这一认识将反过来指导诱变和定向进化实验的设计。我们对适应多样和不断变化的环境的研究将得出广泛适用于在基因型、表型和真实的空间中寻找适应性解决方案的生物学一般原则。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

One remarkable feature of complex life is the ability to survive invasions of threatening microorganisms – a vast and changing variety of them. This relies on the possession of an adaptive immune system that learns from past encounters for future protection. Fast advancing data acquisition techniques have revealed that naturally occurring immune responses are limited in speed, efficacy and capacity to adapt to new challenges, but the origin of which remains poorly understood. This research project will investigate organizing principles behind the emergence of an effective immune response in the presence of functional constraints. By accounting for features unique to native microenvironments, this project will provide a predictive framework for how physical extraction of molecular information at cell-cell interfaces shape the evolutionary driving forces of adaptive immunity, advancing our understanding of molecular recognition in living organisms. In this project, the Principal Investigator (PI) will combine theory and experimental data to explain and predict how antibody repertoires respond to related antigens, providing key insights for developing universal vaccines against rapidly evolving pathogens. The proposed research activities will be closely integrated with education and outreach efforts to provide opportunities for exploring the physics of living systems. A core element is an active engagement of young students with quantitative approaches that span multiple traditional fields. Through a partnership with the UCLA Center X Science Project, the PI will develop interactive online learning modules to engage high-school students and teachers in under served school districts with computational modeling of complex systems. To provide first-hand research experience in her lab, the PI will continue to mentor and recruit underrepresented college students through the Science Exchange program at UCLA. To create a sense of community for young scientists, the PI will host biophysics researchers at various stages of their career to speak at the Center for Biological Physics Seminar series. The PI will engage the public via a workshop at the Institute for Pure and Applied Mathematics and a booth at the Exploring Your Universe event on campus. Major advances of experimental techniques in the past decade has revealed two sources of constraints -- physical and evolutionary – on rapid emergence of an effective immune response in organisms of varying complexity. But until recently we still lack a quantitative framework to determine the functional impact of these constraints and the extent to which cells can control and harness them for adaptation. In this project, the PI will couple theoretical and computational modeling with analysis of biophysical and mutagenesis data to elucidate the limit and potential of immune adaptation to complex antigenic environments. Two focuses are (i) developing first-principles predictions for why immune cells use active processes to physically extract antigen from other cell surface; and (ii) extending theoretical frameworks from statistical physics to characterize evolutionary pathways and adaptive capacity of immune repertoires under diverse and dynamic selection pressure. Theoretical predictions will be tested by collaborating groups probing physical and evolutionary constraints, respectively. Through development of a scale-bridging model framework, this study will provide a first demonstration of the role played by intracellular force generation in modulating natural selection of cell populations, laying the ground for a comprehensive understating of evolution of molecular recognition. Over the course of this project, the PI will construct and validate new measures for detecting the rich structure of epistatic landscapes and explore its evolutionary consequences, in order to bridge the gap between theory and experiment of evolutionary dynamics on rugged fitness landscapes. This understanding will in turn guide the design of mutagenesis and directed evolution experiment. Our study of adaptation to diverse and changing environments will derive general principles that apply broadly to biological search for adaptable solutions in genotype, phenotype, and real space.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.