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

1335822 PI：Kasting 1335835 PI：Nitsche 1335869 PI：Nitsche 1335869详细了解分子通过皮肤吸收的机理，对经皮和局部药物开发的不断发展的需求以及化学品暴露的风险评估至关重要。 该项目解决了目前的主要科学障碍，以便更可靠地预测皮肤组织中的瞬时药物/化学品吸收量和浓度以及全身吸收，所有这些都涉及各种尺度的多相运输过程。 具体而言，它将：（i）产生角质层的显著高级模型（SC，最外屏障）层，包括在角质细胞相中具有可逆角蛋白结合的溶质扩散、脂质相中的扩散各向异性以及比目前考虑的更具体的SC多孔途径的表示;（ii）扩展SC下方有活力表皮的定量扩散模型以包括细胞内和细胞外蛋白结合;和（iii）开发通过下层真皮的胶原/蛋白聚糖基质的受阻溶质扩散的真实模型。 这套有战略针对性的理论和计算发展，由选定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品的广泛工业应用直接相关，对于提供所需的科学知识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的药剂学小组与布法罗的纽约州立大学和芝加哥的伊利诺伊大学的两个PI的微观运输小组之间的合作。 这个GOALI项目的工业合作PI是在宝洁公司。 凭借工业合作伙伴的技术投入和经验，所产生的科学将被纳入一个可访问和透明的计算平台，该平台可以被产品开发，毒理学和监管机构所理解。该项目将推进药物/化学品通过皮肤的运输科学，这对于致力于保护公众健康同时通过新产品开发促进商业利益的工业公司（特别是化妆品和个人护理公司，如GOALI合作伙伴PG）具有实质性的商业价值&。 该技术的主要设想应用是一种改进的、用户友好的皮肤风险评估计算机工具，鉴于目前和可预见的对动物试验的限制，这一点特别重要。 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，粗粒化，方法，从而在细胞水平上的药物/化学品运输的微观细节可以成功地纳入到整体结果的预测，例如，化学品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之类的开放性理论问题，在生物系统中，分子经常与它们移动的组织结合和分离。 更广泛的携带到生物学的其他领域具体绘制在该项目中;这些包括（i）通过细胞间孔的细胞通讯的结合的影响，和（ii）脂质中的分子运动，包括低温生物学的应用。这项研究的具体方面将被剥离到工程，制药科学和公共卫生的本科和研究生课程。最后，高中外展和招聘代表性不足的群体将利用（i）目前的NSF S-STEM赠款支持需要为基础的奖学金在一个共同PI？的部门，和（ii）在当地AIChE部分的专业工程师。

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.