BRIGE: Colloidal scavengers for the reversal of drug toxicity

主要研究者：Akpa提案编号：1228035由于药物中毒导致的智力死亡经常发生，从1999年到2007年的8年期间，其发生率上升了145%。中毒后猝死在意外伤害死亡类别中仅次于机动车事故。这些意外中毒中的绝大多数（93%）是由于药物中毒，最常见的罪魁祸首是处方药。大多数危及生命的麻醉品没有特定的药理解毒剂。由于意外中毒的发生率继续上升，显然有必要制定治疗方法，减轻有毒药物浓度的急性影响。局部麻醉剂过量的病例为治疗对标准复苏措施无反应的药物过量提供了可能的“银弹”。静脉内水包油制剂通常在医院中用作IV营养来源，具有使因其他致命中毒而遭受心脏骤停的患者复苏的潜力。本提案的目的是确定决定脂肪乳剂制剂与靶毒素成功偶联的因素，以减少组织对药物的暴露，从而促进药物过量后的复苏。药物-脂质结合特征的体外测量将与生理药物分布的宏观模型和药物-脂质层相互作用的分子尺度研究相结合，全面探讨脂质清除剂逆转心脏组织中毒素积累的潜力。科学更广泛的影响提高对亲脂分子与心脏组织的本质非特异性结合的理解磷脂层（或通过磷脂层的运输）可用于开发特定于清除应用的胶体制剂。预计成功的非特异性胶体清除剂“特别是高度生物相容性的”将产生广泛的影响。例如，这种药剂可被用作逆转诸如有机磷等化学战剂的毒性的潜在手段。这些化合物也被用作杀虫剂，在发展中国家，它们经常是故意和意外中毒的罪魁祸首。此外，有显着的兴趣，在采用脂滴作为车辆的生物相容性交付的水溶性差的compounds.Broadening参与：拟议的科学Siphon（S2）计划是一个多层次的指导倡议。该计划将强调工程师在解决社会最大挑战方面发挥的积极作用，作为吸引代表性不足的群体进入工程学科的途径。妇女和少数民族在作出教育和职业决定时，往往考虑到其职业选择对其社区的影响。S2旨在影响从高中到研究生水平的参与者对工程作为一个多方面，对社会有影响力的职业的认识。参与者将包括PI作为领导者或家长，研究生作为哥哥姐姐，本科生作为弟弟妹妹（UIC的工程专业学生和当地社区学院的理科学生）。 S2家庭还将包括K-12教师，他们将担任教学顾问，将我们计划的社会工程师项目模块与伊利诺伊州科学学习标准相结合。每个组在层级结构中都有一个位置，对应不同的职责。这种结构将提供向下指导和同侪指导的机会，并应导致“连通性”的感觉，这已被证明是重要的学生保留。

PI: AkpaProposal Number: 1228035Intellectual Merit Fatalities due to drug intoxication occur frequently and their incidence rose 145% in the 8 year period from 1999-2007. Sudden death following poisoning is second only to motor vehicle accidents in causing fatalities within the category of death due to unintentional injury. The vast majority of these unintentional poisonings (93%) are due to drug intoxication and the most frequent culprits are prescription drugs. Most life-threatening intoxicants do not have a specific pharmacological antidote. As the incidence of unintentional poisonings continues to rise, there is clearly a need to develop treatment modalities that mitigate the acute effects of toxic drug concentrations. The case of local anesthetic overdose has presented a possible "silver bullet" for the treatment of drug overdoses that are unresponsive to standard resuscitation measures. Intravenous oil-in-water formulations, commonly used in hospitals as a source of IV nutrition, have the potential to resuscitate patients suffering cardiac arrest due to otherwise fatal poisonings. The objective of this proposal is to identify the factors that determine successful coupling of a lipid emulsion formulation and a target toxin for the purposes of reducing tissue exposure to drugs and, consequently, facilitating resuscitation following drug overdose. In vitro measures of drug-lipid binding characteristics will be combined with macroscale models of physiological drug distribution and molecular scale studies of drug-lipid layer interactions to comprehensively probe the potential of a lipid scavenger to reverse the accumulation of toxins in cardiac tissues.Scientific Broader Impacts An improved understanding of the nature non-specific binding of lipophilic molecules with (or transport through) phospholipid layers may be used to develop colloidal formulations specific to scavenging applications. It is anticipated that a successful non-specific colloidal scavenger " particularly a highly biocompatible one " will have broad impacts. Such an agent could, for example, be exploited as a potential means of reversing toxicity due to chemical warfare agents such as organophosphates. These same compounds are also used as pesticides and, in developing nations, are frequent culprits in intentional and accidental poisonings. Furthermore, there is significant interest in employing lipid droplets as vehicles for biocompatible delivery of poorly water-soluble compounds.Broadening participation: The proposed Science Siblings (S2) program is a multi-level mentoring initiative. The program will emphasize the positive role engineers play in addressing society's greatest challenges as a pathway to attracting under-represented groups into engineering disciplines. Both women and minorities often consider the impact their career choice will have on their communities when making education and career decisions. S2 aims to impact awareness of engineering as a multi-faceted, socially impactful profession amongst participants from the high school to the graduate level. Participants will include the PI as a leader or parent, graduate students as elder siblings, and undergraduate students as younger siblings (engineering students at UIC and science students from local community colleges). The S2 family will also include K-12 teachers who will act as pedagogy advisors regarding the integration of our planned Engineer in Society project modules with Illinois Learning Standards for Science. Each group has a place in the hierarchy that corresponds to different responsibilities. The structure will provide opportunities both for downward mentoring and for peer-to-peer mentoring and should lead to the feeling of "connectedness" that has been shown to be important in student retention.