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且不断变化。这依赖于一种适应性免疫系统，它可以从过去的遭遇中吸取教训，为未来提供保护。快速发展的数据采集技术表明，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，但对其起源仍然知之甚少。本研究项目将研究在存在功能限制的情况下产生有效免疫反应的组织原理。通过考虑原生微环境的独特特征，该项目将为细胞-细胞界面上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，促进我们对生物体分子识别的理解。在这个项目中，首席研究员（PI）将结合理论和实验数据来解释和预测抗体库如何对相关抗原作出反应，为开发针对快速进化的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努力密切结合，为探索生命系统的物理学提供机会。一个核心要素是让年轻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X科学项目中心的合作，PI将开发交互式在线学习模块，让服务不足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项目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意识，PI将邀请处于职业生涯不同阶段的生物物理学研究人员在生物物理中心系列研讨会上发言。PI将通过在纯粹与应用数学研究所举办的研讨会以及在校园“探索你的宇宙”活动中设立一个展位来吸引公众。在过去十年中，实验技术的重大进展揭示了在不同复杂性的生物体中快速出现有效免疫反应的两个限制来源——物理和进化。但直到最近，我们仍然缺乏一个定量的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适应的程度。在这个项目中，PI将把理论和计算模型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局限性和潜力。两个重点是：(i)发展第一性原理预测为什么免疫细胞使用主动过程物理地从其他细胞表面提取抗原；（ii）扩展统计物理学的理论框架，以表征免疫库在多样化和动态选择压力下的进化途径和适应能力。理论预测将分别由探索物理和进化限制的合作小组来检验。通过开发一个尺度桥接模型框架，本研究将首次展示细胞内力产生在调节细胞群体自然选择中所起的作用，为全面理解分子识别的进化奠定基础。在这个项目的过程中，PI将构建和验证检测上位性景观丰富结构的新措施，并探索其进化后果，以弥合崎岖适应度景观进化动力学理论和实验之间的差距。这种认识将反过来指导诱变和定向进化实验的设计。我们对适应多样化和不断变化的环境的研究将得出一般原则，这些原则广泛适用于在基因型、表型和实际空间中寻找适应性解决方案的生物学研究。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.