Collaborative Research: GOALI: Multiscale Theory and Computer Simulation of Skin Absorption Phenomena

1335822π:Kasting1335835π:Nitsche1335869PI: NitscheDetailed机械的理解分子通过皮肤吸收至关重要的发展需要经皮肤和局部药物开发,和化学物质的风险评估。该项目解决了目前主要的科学障碍，以更可靠地预测皮肤组织中瞬时药物/化学物质的吸收量和浓度以及全身吸收，所有这些都涉及不同规模的多相运输过程。具体来说，它将：(i)产生一个非常先进的角质层（SC，最外层屏障）层模型，包括角质层内可逆角蛋白结合的溶质扩散，脂质期的扩散各向异性，以及比目前认为的更具体的SC多孔途径的表征；（ii）扩展SC以下活表皮的定量扩散模型，以包括细胞内和细胞外蛋白质结合；（iii）建立一个现实的模型，通过真皮下的胶原/蛋白多糖基质阻碍溶质扩散。这一有战略针对性的理论和计算发展，通过选定的实验数据，将极大地提高定量预测皮肤吸收参数的能力。这些参数与制药和消费品中的广泛工业应用直接相关，并且对于提供必要的科学以告知和满足不断变化的化学品风险监管要求也至关重要。在学术方面，该项目是辛辛那提大学PI的制药组与纽约州立大学布法罗分校和伊利诺伊大学芝加哥分校PI的两个微观运输组之间的合作。这个目标行动计划的工业合作伙伴是宝洁公司（Procter & Gamble）。有了工业合作伙伴的技术投入和经验，产生的科学将被纳入一个可访问的透明计算平台，供产品开发、毒理学和监管界理解。该项目将推进药物/化学物质通过皮肤运输的科学，这对致力于保护公众健康的工业公司（特别是化妆品和个人护理公司，如GOALI的合作伙伴P&amp；G）具有重大的商业价值，同时通过新产品开发促进商业利益。该技术的主要设想应用是一种改进的、用户友好的计算机工具，用于皮肤风险评估，鉴于目前和可预见的动物试验限制，这一点特别重要。该工具将通过提案中讨论的披露机制向公众、其他公司和政府机构提供。更广泛的医学影响包括深入了解接触致敏和皮肤药物活性的机制。该项目的核心要素之一是理论上的粗粒度方法，通过这种方法，细胞水平上药物/化学运输的微观细节可以成功地纳入对总体结果的预测，例如，化学暴露或药物贴片的应用。部分分析将回答诸如如何在生物系统中进行粗粒化这样的开放性理论问题，在生物系统中，分子经常与它们所经过的组织结合和分离。更广泛的延续到生物学的其他领域是具体规划在项目中；这些包括(i)通过细胞间孔隙对细胞通讯的结合效应，以及（ii）脂质中的分子运动，包括在低温生物学中的应用。这项研究的具体方面将分拆成工程、制药科学和公共卫生的本科和研究生课程。最后，高中拓展和从代表性不足的群体中招聘将利用(i)当前的NSF S-STEM资助，支持co-PI之一的基于需求的奖学金？的部门，以及（ii）本地AIChE组的专业工程师。

1335822 PI: Kasting1335835 PI: Nitsche1335869PI: NitscheDetailed mechanistic understanding of molecular absorption through the skin is critical to the evolving needs of transdermal and topical drug development, and risk assessment of chemical exposures. This project addresses the primary current scientific stumbling blocks for more reliable prediction of transient drug/chemical absorbed amounts and concentrations in skin tissue as well as systemic absorption, all involving multiphase transport processes at various scales. Specifically, it will: (i) produce a significantly advanced model of the stratum corneum (SC, outermost barrier) layer, including solute diffusion with reversible keratin binding within the corneocyte phase, diffusional anisotropy within the lipid phase, and more concrete representations of the SC porous pathway than are currently considered; (ii) extend a quantitative diffusion model of the viable epidermis below the SC to include intra- and extracellular protein binding; and (iii) develop a realistic model of hindered solute diffusion through the collagen/proteoglycan matrix of the underlying dermis. This strategically targeted set of theoretical and computational developments, informed by selected experimental data, will materially advance the ability to quantitatively predict skin-absorption parameters. Such parameters are directly relevant to a broad spectrum of industrial applications in pharmaceutical and consumer products, and are also critical to supplying the science needed to inform and satisfy evolving regulatory requirements for chemical risk. On the academic side the project is collaboration between the pharmaceutics group of the PI at the University of Cincinnati, and the microscopic transport groups of two PIs at the State University of New York at Buffalo and the University of Illinois at Chicago. The industrial co-PI for this GOALI project is at Procter & Gamble. With the technical input and experience of the industrial partner, the science generated will be incorporated into an accessible and transparent computational platform that can be understood by the product development, toxicology, and regulatory communities.This project will advance the science of drug/chemical transport through skin, which is of substantial commercial value to industrial corporations (especially cosmetic and personal care companies such as the GOALI partner P&G) dedicated to preserving the public health while advancing business interests through new product development. The primary envisioned application of the technology is an improved, user-friendly computer tool for dermal risk assessment that is of particular importance in light of current and foreseeable restrictions on animal testing. This tool will be made available to the general public, other companies and government agencies by the disclosure mechanisms discussed within the proposal. Broader medical impacts include insights into the mechanism of contact sensitization and dermal drug activity. One of the central elements of the project is the theoretical, coarse-graining, method, whereby microscopic details of drug/chemical transport at the cellular level can be successfully incorporated into predictions of the overall outcome of, for example, a chemical exposure or the application of a drug patch. Parts of the analysis will answer such open theoretical questions as how to carry out coarse-graining in biological systems, where molecules frequently bind and unbind to the tissues through which they move. Broader carry over to other areas of biology are concretely mapped out in the project; these include (i) effects of binding on cellular communication through intercellular pores, and (ii) molecular motion in lipids, including applications to cryobiology. Specific aspects of this research will be spun off into undergraduate and graduate curricula in engineering, pharmaceutical sciences and public health. Finally, high school outreach and recruiting from underrepresented groups will leverage (i) a current NSF S-STEM grant supporting need-based scholarships in one of the co-PI?s departments, and (ii) professional engineers in the local AIChE section.