Micro-scale Transport as a Critical Link between Molecular-scale Absorption and Macro-scale Mixing in Gut Physiology and Function

建议没有。微尺度运输是肠道生理学和功能中分子尺度吸收和宏观尺度混合之间的关键环节，小肠的消化和药物功效取决于源自粘膜上皮的大流量分子的运输，以及分泌分子在1-2厘米尺度上的大流量混合运输。吸收和分泌受到分子向上皮细胞的扩散的限制，上皮细胞覆盖着大量的指状突起或绒毛（约100-500微米），绒毛排列在肠粘膜上。上皮细胞依次排列有直接参与吸收的“微绒毛”（大小约为1微米）。因此，消化过程依赖于跨越几个数量级的高度耦合的多尺度输运和混合过程。本研究将重点关注吸收和分泌的细节和神经生理控制，通过系统模型，整合从宏观混合到分子吸收的整个尺度，以绒毛诱导的微运输为中心，作为吸收的关键环节。将宏微观耦合模型与动物实验相结合，利用微线圈磁共振成像（MRI）定量体内粘膜和绒毛的时空运动。PI将开发一类新的算法，将双尺度晶格玻尔兹曼（LB）、分子动力学（MD）和移动边界结合起来。建模与实验的协调可以产生以前从未发现的关键知识。这是一种独特的方法来分析医学上重要的生理系统（肠道吸收）。研究领域对医学科学和临床实践的重要性怎么强调都不为过。许多重大疾病都与胃肠道有关，其中大多数通过改变吸收和/或分泌来影响消化。从科学上讲，这个项目有潜力打开一个潜在的重要研究的新领域，对基础生理学、疾病、临床评估和治疗有影响。研究团队包括在建模、实验和MRI技术方面具有专业知识的生物工程师、GI细胞和分子神经生理学家、LB专家和临床科学家之间的新合作。研究生和本科生将在一个高度跨学科的项目中接受培训，这些项目涉及非常不同的学科领域（生理学、力学和医学）和方法（建模、实验和IT）。通过这个项目，PI将培养生理学和医学方面的工程师，以及工程学原理方面的生理学家和临床科学家。特别关注的是本科生，PI的目标是激发优秀学生继续接受更高水平的教育，同时向新的跨学科方向发展。将征聘代表性不足的群体的成员，以便特别鼓励他们参与最高级别的跨学科教育、科学分析和技术进步。

PROPOSAL NO.: 0506215PRINCIPAL INVESTIGATOR: J. BrasseurINSTITUTION NAME: Pennsylvania State UniversityMICRO-SCALE TRANSPORT AS A CRITICAL LINK BETWEEN MOLECULAR-SCALE ABSORPTION AND MACRO-SCALE MIXING IN GUT PHYSIOLOGY AND FUNCTIONDigestion and pharmaceutical efficacy of the small bowels depends on the transport of molecules originating in the bulk flow across the mucosal epithelium, and the transport of secreted molecules to the bulk flow with macro mixing at the 1-2 cm scale. Absorption and secretion are rate-limited by diffusion of molecules to/from epithelial cells covering multitudes of finger-like protuberances, or "villi" (approximately 100-500 microns in scale) that line the gut mucosa. The epithelial cells are, in turn, lined with "microvilli" (on the order of 1 micron in scale) directly involved in absorption. The process of digestion therefore relies on highly coupled multi-scale transport and mixing processes that span several orders of magnitude. The research will focus on the details and neurophysiological controls of absorption and secretion through systems models that integrate the entire range of scales from macro-mixing to molecular absorption, centering on villi-induced micro-transport as a critical link to absorption. Coupled macro- to micro- models will be integrated with animal experiments in which micro-coil magnetic resonance imaging (MRI) will be used to quantify space-time mucosal and villi motion in vivo. The PI's will develop a new class of algorithms that couple dual-scale lattice-Boltzmann (LB), molecular dynamics (MD) and moving boundaries. The coordination of modeling with experiment can yield critical knowledge never before uncovered. This is a unique approach to analyze a medically important physiological system (gut absorption). The importance of the area of research to medical science and clinical practice cannot be over stated. Many major diseases are associated with the GI tract, and most of these affect digestion through alterations in absorption and/or secretion. Scientifically, this program has the potential to open a new area of potentially important research with implications to basic physiology, disease, clinical evaluation, and treatment. The research team includes new collaborations among bioengineers with expertise in modeling, experiment, and MRI technology, a GI cellular and molecular neurophysiologist, an LB expert, and a clinical scientist. Graduate and undergraduate students will be trained in a highly interdisciplinary program both across very different subject areas (physiology, mechanics, and medicine) and across methodologies (modeling, experiment, and IT). Through this program The PI's will train engineers in physiology and medicine, and physiologists and clinical scientists in the principles of engineering. A particular focus will be on the undergraduate students where the PI's aim to excite exceptional students to go on to higher levels of education while moving in new interdisciplinary directions. Members of underrepresented groups will be recruited in order to provide particular encouragement for their involvement in the highest levels of interdisciplinary education, scientific analysis, and advances in technology.