MPS-BIO: Collaborative Research: Physical Mechanisms Regulating Sperm Chemotaxis

尽管经过了一个世纪的深入研究，受精仍然是最不为人所知的基本生物过程之一。配子之间的化学信号通过液体传播的线索发生在具有高度不同生殖策略的不同分类群中，被认为在生殖中起着重要作用。然而，配子之间的化学通讯在自然条件下是如何发生的尚不清楚。化学线索的有效性及其对雄性配子运动的影响的关键决定因素是环境流体运动。流体运动可能通过将配子聚集在一起来促进细胞相互作用，或者交替抑制粘附和结合，但对于流体对雄性配子的运动和趋化性的影响知之甚少。现有的方法研究物理和化学在配子行为和受精中的作用的能力有限。在微观尺度上精确控制流体运动和化学线索是非常困难的。在这个项目中，最先进的微流体方法将使对配子自然居住的微环境的空前控制成为可能。本研究将采用综合方法并应用微流体来确定物理和化学在配子相互作用中的作用。这项拟议的研究将在私人研究员Jeff Riffell（华盛顿大学）、Roman Stocker（麻省理工学院）和Richard Zimmer（加州大学洛杉矶分校）的指导下进行，因此围绕两个主要目标进行：(i)确定化学线索对雄性配子运动和受精成功的影响；（二）确定流体运动对雄性配子运动的影响及其对化学线索的反应。三个pi之间的专业知识的协同作用和互补性将使深入表征雄性配子游泳的生物力学和生殖细胞之间的化学通讯。这项研究的综合和跨学科的方法将对科学和社会产生广泛而多样的影响。微流控技术的应用将有助于更好地了解雄性配子趋化性，并为生殖和保护生物学提供新的知识。与此同时，本研究在实现流体流动和化学线索的微观控制方面所取得的进展将为生物学的不同领域提供广泛的方法框架。本研究将物理、生物和化学紧密结合，为高中、本科和研究生阶段的学生提供充足的培训机会，强调科学领域代表性不足的群体，通过(1)与华盛顿大学生命科学暑期学院（SILS）的合作，为期4周的动手暑期学院，为4-8年级的教师提供研究经验；(2)通过麻省理工学院的Edgerton中心外展计划提供3小时的科学体验，旨在促进高中生的科学实践经验；(3)每季度在加州大学洛杉矶分校开设一个新的课程模块，并让3-4名加州大学洛杉矶分校本科生参与研究；这些本科生将通过加州大学洛杉矶分校学术与研究卓越中心和加州大学洛杉矶分校高级学位卓越领导力项目从代表性不足的群体中选拔；(4)培养细胞生物学和微流体学方面的研究生和博士后。总之，这些项目将在多个教育层次促进外展和科学教育。按照所有三个项目规划的传统，在技术和大众文献中广泛传播成果，将补充这一外联计划。

Despite a century of intensive research, fertilization is one of the least understood fundamental biological processes. Chemical signaling between gametes through fluid-borne cues occurs in diverse taxa with highly divergent reproductive strategies and is thought to play a fundamental role in reproduction. Still, it is unclear how chemical communication between gametes occurs under natural conditions. A critical determinant of the effectiveness of chemical cues and their influence on the motility of male gametes is ambient fluid motion. Fluid motion may promote cell interactions by bringing gametes together or alternately may inhibit adhesion and binding, yet very little is known about the effects of flow on the motility and chemotaxis of male gametes. Existing methods have limited ability to study the role of physics and chemistry in mediating gamete behavior and fertilization. It is very difficult to accurately control fluid motion and chemical cues at microscopic scales. In this project, state-of-the-art microfluidic approaches will enable unprecedented control over microenvironments naturally inhabited by gametes. This study will take a comprehensive approach and apply microfluidics to determine the roles played by physics and chemistry in gamete interactions. The proposed research, to be carried out under the guidance of PIs Jeff Riffell (U. Washington), Roman Stocker (MIT) and Richard Zimmer (UCLA), is thus structured around two principal aims: (i) determine the impact of chemical cues on male gamete motility and on fertilization success; (ii) establish the effects of fluid motion on the motility of male gametes and their response to chemical cues. The synergy and complementarity of expertise between the three PIs will enable an in-depth characterization of the biomechanics of male gamete swimming and of chemical communication between germ cells. The comprehensive and interdisciplinary approach of this study will have broad and diverse impacts on science and society. A better understanding of male gamete chemotaxis will arise from the use of microfluidic technology and provide new knowledge on reproduction and conservation biology. At the same time, the advances fostered by this study in attaining control of fluid flow and chemical cues at the microscale will provide a broad methodological framework for diverse areas of biology. The intimate combination of physics, biology and chemistry in this study will provide ample training opportunities for students at high school, undergraduate and graduate levels, emphasizing under-represented groups in science, through (1) a collaboration with the Summer Institute for Life Science (SILS) at the University of Washington, a 4-week hands-on summer institute that provides grade 4-8 teachers with research experience; (2) the development of a 3-hour science experience to be offered through MIT's Edgerton Center Outreach Program, designed for high-school students to promote hands-on experience in science; (3) the creation of a new course module at UCLA and the involvement of 3-4 UCLA undergraduates in research, each quarter; these undergraduates will be drawn from underrepresented groups through the UCLA CARE (Center for Academic and Research Excellence) and the UC LEADS (Leadership Excellence through Advanced DegreeS) Programs; and (4) the training of graduate students and postdoctorates in cell biology and microfluidics. Together, these programs will foster outreach and science education at multiple educational levels. Broad dissemination of results in technical and popular literature, in the tradition of all three PIs, will complement this outreach plan.