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

1335822 PI：Kasting1335835 PI：Nitsche1335869PI：NitscheKasting1335835PI：Nitsche1335869PI：Nitsche13该项目针对目前更可靠地预测皮肤组织和全身吸收的瞬时药物/化学品吸收数量和浓度以及全身吸收的主要科学绊脚石，所有这些都涉及不同规模的多相传输过程。具体地说，它将：(I)产生一个非常先进的角质层(SC，最外层屏障)层的模型，包括角质在角质细胞相内可逆角蛋白结合的扩散，在脂类相内的扩散各向异性，以及SC多孔途径的比目前认为的更具体的表示；(Ii)扩展SC下有活力的表皮的定量扩散模型，以包括细胞内和细胞外的蛋白质结合；以及(Iii)开发一个现实的通过底层真皮的胶原/蛋白多糖基质的受阻溶质扩散模型。这套具有战略针对性的理论和计算发展，由精选的实验数据提供信息，将大大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产品的广泛工业应用直接相关，对于提供所需的科学信息和满足不断变化的对化学风险的监管要求也是至关重要的。在学术方面，该项目是辛辛那提大学PI的制药小组与纽约州立大学布法罗分校和芝加哥伊利诺伊大学两个PI的微观运输小组之间的合作。这个Goali项目的工业合作伙伴是宝洁。在工业伙伴的技术投入和经验下，产生的科学将被纳入一个可访问和透明的计算平台，产品开发、毒理学和监管团体可以理解。该项目将促进药物/化学物质通过皮肤运输的科学，这对工业公司(特别是化妆品和个人护理公司，如Goali合作伙伴宝洁)具有重大的商业价值，致力于保护公众健康，同时通过新产品开发促进商业利益。这项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，这一工具特别重要。这一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对接触致敏机制和皮肤药物活性的洞察。该项目的核心要素之一是理论上的粗粒化方法，通过这种方法，可以成功地将细胞一级药物/化学运输的微观细节纳入对例如化学暴露或药物贴片应用的总体结果的预测。部分分析将回答诸如如何在生物系统中进行粗粒化等悬而未决的理论问题，在生物系统中，分子经常与其运动所通过的组织结合和解绑。该项目具体列出了生物学其他领域的更广泛的影响；这些包括(I)结合对通过细胞间毛孔的细胞通讯的影响，以及(Ii)脂类中的分子运动，包括在低温生物学中的应用。这项研究的具体方面将被分成工程、制药科学和公共卫生的本科生和研究生课程。最后，高中外展和从代表性不足的群体中招聘将利用：(I)目前的国家科学基金会S-STEM补助金，支持S与S合办的一个部门的基于需要的奖学金，以及(Ii)当地AIChE部门的专业工程师。

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.