A NEW TECHNIQUE FOR TREATING HEMORRHAGIC SHOCK

描述（由申请人提供）：本提案的具体目的是使用新开发的细胞内能量输送技术来增强复苏，并研究组织高能磷酸盐补充与失血性休克期间组织坏死和细胞凋亡之间的关系。 在大多数西方国家，创伤/出血是40岁以下死亡的主要原因。严重创伤和出血的最常见后果是休克，这是一种低血容量状况，其中向身体输送的氧气不足以产生维持组织功能和结构完整性所必需的三磷酸腺苷（ATP）和二磷酸腺苷（ADP）。休克的治疗策略在过去的半个世纪中变化很小，死亡率和发病率仍然很高。几十年前就描述了失血性休克期间高能磷酸盐的消耗，一些作者报道直接给予游离Mg-ATP可增加组织ATP浓度、组织和线粒体Mg水平以及细胞功能。然而，这种方法是有争议的，不仅因为保护作用不能总是被其他科学家复制，而且因为ATP在血液循环中的半衰期很短-不到40秒。此外，众所周知，像ATP这样的高电荷分子通常不会穿过细胞膜。我们已经开发了一种用于细胞内Mg-ATP递送的技术（称为ATP囊泡或VitaSolTM）。初步结果表明，在几种组织缺氧和缺血模型中，包括休克，具有非常有希望的效果。我们的假设是，细胞内ATP水平的补充减轻或消除了失血性休克引起的许多不利影响，从而增加了生存时间。 本I期计划有两个目的：1）确定VitaSolTM治疗对失血性休克的影响; 2）研究失血性休克期间组织高能磷酸盐含量与坏死和凋亡之间的关系，以及VitaSolTM治疗对这些变化的影响。这些研究过去未进行过。该项目的成功将可能为严重创伤和休克的治疗提供一种全新的治疗方法。对这种新的能量输送技术的进一步研究也可能有益于各种临床病症，例如冠心病、中风、脊髓损伤、心肺转流术、器官移植、慢性伤口和涉及缺血的许多其他病症。对医学的潜在影响很大。 公共卫生相关性：在大多数西方国家，创伤/出血是40岁以下死亡的主要原因，但尚未开发出有效的治疗方法，死亡率仍然很高。本研究的目的是利用我们新开发的细胞内能量传递技术来加强失血性休克的复苏。该项目的成功可能会对医学产生重大影响。

DESCRIPTION (provided by applicant): The specific aims of this proposal are to use a newly developed intracellular energy delivery technique to enhance resuscitation, and to study the relationship between tissue high-energy phosphate supplementation and tissue necrosis and apoptosis during hemorrhagic shock. In most western countries, trauma/hemorrhage is the leading cause of death up to the age of 40. The most common consequence of severe trauma and hemorrhage is shock, which is a hypovolemic condition in which oxygen delivery to the body is inadequate for the generation of the adenosine triphosphate (ATP) and adenosine diphosphate (ADP) necessary to maintain the function and structural integrity of tissues. Treatment strategies for shock have changed very little in the past half century and the incidence of mortality and morbidity remains very high. Depletion of high-energy phosphates during hemorrhagic shock was described decades ago, and direct administration of free Mg-ATP was reported to increase tissue ATP concentrations, tissue and mitochondrial Mg levels, and cellular functions by some authors. However, this approach is controversial, not only because the protective effects cannot always be duplicated by other scientists, but also because the half life of ATP is very short in the blood circulation-less than 40 seconds. Furthermore, it i well known that highly charged molecules like ATP do not normally cross the cell membrane. We have developed a technique for intracellular Mg-ATP delivery (named ATP- vesicles or VitaSolTM). Preliminary results have indicated a very promising effect in several models of tissue hypoxia and ischemia, including shock. Our hypothesis is that the replenishment of intracellular ATP levels alleviates or eliminates many of the detrimental effects caused by hemorrhagic shock, thereby increasing survival time. This Phase I proposal has two aims: 1) To establish the effect of VitaSolTM treatment on hemorrhagic shock; and 2) To investigate the relationship between tissue high- energy phosphate contents and necrosis and apoptosis during hemorrhagic shock, and the effect of VitaSolTM treatment on these changes. These studies have not been performed in the past. The success of this project will likely provide a totally new therapeutic approach for treatment of severe trauma and shock. Further study of this new energy delivery technique may also benefit various clinical conditions, such as coronary heart disease, stroke, spinal cord injury, cardiopulmonary bypass, organ transplant, chronic wounds, and many other conditions where ischemia is involved. The potential impact on medicine is high. PUBLIC HEALTH RELEVANCE: Trauma/hemorrhage is the leading cause of death up to the age of 40 in most western countries, but no effective treatment has been developed and mortality remains very high. This proposal is to use our newly developed intracellular energy delivery technique to enhance resuscitation in hemorrhagic shock. The success of this project will likely have a major impact on medicine.