Uncovering microbial modulators of neuroactive molecules as novel therapeutics.

描述（由申请人提供）：人类被不同的微生物群落定植，统称为共生微生物群，影响广泛的生物过程。最近的研究表明，除了在营养、免疫和代谢方面的作用外，共生微生物群在神经系统的发育和功能以及一些复杂的宿主行为中也起着重要作用。本研究旨在揭示特定共生微生物与神经系统相互作用的机制，并阐明这些关系对宿主生理的影响。具体而言，本研究将研究共生微生物对宿主5-羟色胺（5-hydroxytrypatmine, 5-HT）代谢的作用，旨在确定受共生微生物影响的5-HT通路的具体步骤，确定影响宿主5-HT的特定微生物种类和因素，并应用这些微生物5-HT调节剂改善5-HT相关疾病模型的症状。这些研究的发现将促进我们目前对共生微生物群如何影响健康和疾病的理解，并将进一步探索开发新的基于微生物的治疗方法的创新前景，这些治疗方法可以很容易地进行修改，以获得更好的功能、调节控制、靶向和递送。共生微生物群与神经系统之间相互作用的研究填补了一个新的多学科研究领域，不仅包括神经生物学和微生物学，还包括生物化学（5-HT通路分子变化的解剖）、化学工程（用于高通量限制的微流体装置的纳米制造）、生物化学（用于高通量限制的微流体装置的纳米制造）和生物化学（用于高通量限制的微流体装置的纳米制造）。微生物组内源性物种的培养和功能筛选)以及分子和行为神经科学（研究血清素缺乏小鼠模型的病理）。我提议的培训将跨越五年，作为加州理工学院的高级研究员进行独立研究。这个头衔通常是为有博士后经验的个人保留的，并作为晋升到初级教师职位的过渡阶段。大约在授予该奖项一年后；我将招聘一名全职技术人员，具有丰富的实验室研究经验。我还将开始通过加州理工学院的暑期研究项目，每年指导至多两名生物或化学本科生。

DESCRIPTION (provided by applicant): Humans are colonized with diverse microbial communities, collectively called the commensal microbiota, that influence a wide array of biological processes. Recent studies demonstrate that in addition to their roles in nutrition, immunity and metabolism, the commensal microbiota also plays a fundamental role in the development and function of the nervous system, in addition to several complex host behaviors. The proposed research training program aims to uncover the mechanisms underlying the interaction between specific commensal microbes and the nervous system, and to elucidate the impact of these relationships on host physiology. Specifically, the proposed research will examine the role of commensal microbes on host serotonin (5-hydroxytrypatmine, 5-HT) metabolism, with aims to define the specific steps of the 5-HT pathway that are affected by commensal microbes, identify the particular microbial species and factors that affect host 5-HT, and apply these microbial 5-HT modulators toward ameliorating symptoms in models of 5-HT-related disease. Findings from these studies will advance our current understanding of how the commensal microbiota affects health and disease, and will further explore the innovative prospect of developing novel, microbe-based therapeutics, which can be readily modified for better function, regulatory control, targeting and delivery. The proposed studies on the interaction between the commensal microbiota and nervous system fills a novel area of multidisciplinary research that integrates not only neurobiology and microbiology, but also biochemistry (in the dissection of molecular alterations in the 5-HT pathway), chemical engineering (in the nanofabrication of microfluidic devices for high-throughput confinement, cultivation and functional screening of endogenous species of the microbiome) and molecular and behavioral neuroscience (in the investigation of pathologies seen in mouse models of serotonin-deficiency). My proposed training will span five years of independent research as a Senior Research Fellow at the California Institute of Technology. This title is typically reserved for individuals with previous post-doctoral experience and serves as a transitional stage toward advancing into a junior faculty position. Approximately one year after the award is conferred; I will recruit one full-time technician, with significant previous experience in laboratory research.I will also begin mentoring up to two biology or chemistry undergraduate students per year through Caltech's summer research program.