Treatment with KZ-41 and OTP promotes wound healing in a radiation combined injur

无论是暴露在核武器下的部队，还是遭受核攻击的平民， 将很可能遭受辐射和机械、血管或热损伤的联合作用。在我们的建议中， 将评估两种新型药物的使用，这些药物可以限制辐射和创伤的有害影响，我们将 目标是受到中等剂量全身照射的个人。我们的新型代理人 由田纳西大学的研究人员开发。在小鼠中照射后12小时内给药 用致死剂量的γ射线照射，十八碳烯基硫代磷酸（OTP）拯救细胞免于死亡， 减轻分泌性腹泻，增加白色血细胞和血小板计数，这一切都放在一起减轻 混合辐射综合症并拯救生命生物医学高级研究和 发展管理局透露，OTP是唯一的低分子量化合物（只有两个之一 目前正在考虑FDA的快速批准。KZ-41，我们的另一种新药，是一种 奎尼酸（QA）的有效类似物，奎尼酸是草药猫爪的热水提取物中的活性成分。 我们的初步数据表明，KZ-41具有有效的血管抗炎作用，促进血管 从受伤中恢复，并增加白色血细胞计数，使其成为一个很好的候选人，作为一个潜在的 促进组织恢复和伤口修复试剂。我们的应用程序的目标是开发一个 治疗策略，将促进暴露于全身照射的个体的生存和伤口愈合 (TBI)遭受创伤性机械损伤。我们的核心假设是，OTP将致力于增加 通过拯救细胞免于程序性细胞死亡（由辐射暴露触发）并启动 血细胞计数增加和KZ-41将阻止由创伤性伤口损伤诱导的炎症 以及通过辐射暴露允许伤口愈合进展到生长阶段和随后的重塑阶段 正常的愈合。 R21阶段具体目标 1.建立放射复合伤大鼠模型。该模型将用于表征 全身照射对伤口愈合、伤口生物力学、微血管损伤和修复的影响， 血液化学和血清细胞因子表达。 2.我们将在临床上测试OTP和KZ-41单独和联合治疗的疗效， 实际上，放射复合伤后的相关时间点（12和24小时）。 R33阶段具体目标 3.我们将研究我们的主要化合物QA的化学变化，以寻找更有效的药物 具有更高的功效。 4.我们将优化我们的新型药物的化学参数，以确保易于使用（如口服）。

Whether it is troops exposed to nuclear weapons or civilians in a nuclear attack, the majority of the survivors will most likely suffer from combined radiation and mechanical, vascular, or thermal injury. In our proposal we will asses the use of two novel agents that limit the harmful effect of combined radiation and trauma and we will target individuals who were exposed to moderate doses of total body irradiation. Our novel agents were developed by researchers at the University of Tennessee. When applied up to 12 h post-irradiation in mice irradiated with lethal doses of γ-irradiation, Octadecenyl thiophosphate (OTP) rescues cells from death, attenuates secretory diarrhea, increases white blood cell and platelet counts, which all put together attenuate the mixed radiation syndrome and save lives. Recent information from the Biomedical Advanced Research and Development Authority reveals that OTP is the only low-molecular-weight compound (and one of only two compounds) currently under consideration for fast-track approval by the FDA. KZ-41, our other novel drug, is a potent analog of quinic acid (QA), which is an active ingredient in hot water extracts of the herbal cat's claw. Our preliminary data indicate that KZ-41 has potent vascular anti-inflammatory effects, promotes vascular recovery from injury, and increases white blood cell count, making it an excellent candidate as a potential agent that facilitate tissue recovery and wound repair. The objective of our application is to develop a treatment strategy that will promote survival and wound healing in individuals exposed to total body irradiation (TBI) who suffer from traumatic mechanical injury. Our central hypothesis is that OTP will work to increase survival by rescuing cells from programmed cell death (triggered by radiation exposure) and initiating an increase in blood cell counts and that KZ-41 will arrest the inflammation induced by the traumatic wound injury and by radiation exposure allowing the wound healing to progress to the growth and then remodeling phases of normal healing. R21 Phase Specific Aims 1. Develop a radiation combined injury rat model. The model will be used to characterize the effect of total body irradiation on wound healing, wound biomechanics, microvascular damage and repair, blood chemistry, and serum cytokine expression. 2. We will test the efficacy of treatment with OTP and KZ-41, separately and combined at clinically, and practically, relevant time points (12 and 24 hours) post radiation combined injury. R33 Phase Specific Aims 3. We will investigate chemical variations of our main compound QA to search for more potent agents with higher efficacy. 4. We will optimize chemical parameters of our novel agents to ensure ease of use (such oral delivery).