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Accelerating Wound Healing through RNAi

通过 RNAi 加速伤口愈合

基本信息

批准号：
8782358
负责人：
Brian H. Johnston
金额：
$ 72.35万
依托单位：
SOMAGENICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-24 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8782358
关键词：
Acute Biological Blood Platelets Cell Culture Techniques Cell Survival Cell physiology Chemicals Chronic Clinical Research Complex Conserved Sequence Cultured Cells Decubitus ulcer Diabetic ulcer Dose Drug Formulations Elderly Endothelial Cells Event Fibroblasts Growth Healed Health Benefit Health Care Costs Heat shock proteins Hepatitis C Hepatitis C virus Human Hypoxia Immigration Immune Impaired wound healing In Vitro Infection Inhibition of Apoptosis Injury Intervention Medical Methods MicroRNAs Modeling Modification Mus Non-Insulin-Dependent Diabetes Mellitus Oligonucleotides Patients Phase Play Population Process Proteins RNA RNA Interference Refrigeration Resistance Risk Role Site Skin Speed Surgical Flaps Testing Therapeutic Therapeutic Effect Thick Time Tissues Transcript Varicose Ulcer Vascular Endothelial Growth Factors Wound Healing angiogenesis base cell type combinatorial design diabetic diabetic wound healing efficacy testing healing high risk improved in vivo inhibitor/antagonist keratinocyte macrophage migration mouse model novel novel therapeutic intervention phase 1 study programs public health relevance response small hairpin RNA success tissue culture transcription factor treatment strategy vasculogenesis wound

项目摘要

DESCRIPTION (provided by applicant): The growing populations of the elderly and those with type-II diabetes are at high risk for developing chronic wounds that are slow to heal. Effective therapeutics to promote wound healing could significantly improve the lives of these people. Normal wound healing involves a coordinated cascade of events that are stimulated in part by the hypoxia that results from injury to the vasculature at the wound site. These events include angiogenesis, vasculogenesis, macrophage recruitment, inhibition of apoptosis, and the expansion and mobilization of fibroblasts and keratinocytes for re- epithelializaton. In chronic wounds, the normal response to hypoxia is impaired and many of these cellular processes are hindered. In this project, we have proposed to modulate three key targets involved these processes using a combination of RNA interference (RNAi) and antisense approaches. In Phase I we identified oligonucleotides that reduce levels of two of these targets (a protein and a microRNA [miRNA]), increase levels of downstream factors promoting angiogenesis, and increase the mobility of keratinocytes. One of these inhibitors uses Somagenics' proprietary sshRNA" (short synthetic hairpin RNA) design, which has been shown to be highly effective in treating chimeric mice infected with hepatitis C virus. In Phase II, we will test the effects of modulating levels of the third target, which is also a miRNA, and evaluate the biological effects of these oligonucleotides when used individually or in combinations in tissue culture models relevant to wound healing. We will then test the in vivo efficacy of these three oligonucleotides under normal as well as compromised (ischemic and diabetic) wound healing conditions in mice. To enhance in vivo stability and eliminate any undesirable immune stimulation, all three oligonucleotides will be chemically modified. In addition, several different methods for delivering RNA to tissue will be evaluated for efficacy in speeding wound closure and effect on the targets of the oligonucleotides as well as downstream factors involved in wound healing. This novel, three-pronged approach to modulating the factors involved in wound healing could represent an effective strategy for treatment of chronic wounds, and potentially also acute wounds.

描述（由申请人提供）：不断增长的老年人口和 II 型糖尿病患者出现愈合缓慢的慢性伤口的风险很高。促进伤口愈合的有效疗法可以显着改善这些人的生活。正常的伤口愈合涉及一系列协调一致的事件，这些事件部分是由伤口部位脉管系统损伤导致的缺氧刺激的。这些事件包括血管生成、血管生成、巨噬细胞募集、细胞凋亡的抑制以及成纤维细胞和角质形成细胞的扩张和动员以进行上皮再生。在慢性伤口中，对缺氧的正常反应受到损害，并且许多细胞过程受到阻碍。在这个项目中，我们建议结合使用 RNA 干扰 (RNAi) 和反义方法来调节涉及这些过程的三个关键靶标。在第一阶段，我们鉴定出寡核苷酸可以降低其中两个靶标（蛋白质和微小RNA [miRNA]）的水平，增加促进血管生成的下游因子的水平，并增加角质形成细胞的流动性。其中一种抑制剂采用Somagenics专有的sshRNA”（短合成发夹RNA）设计，该设计已被证明在治疗感染丙型肝炎病毒的嵌合小鼠方面非常有效。在第二阶段，我们将测试第三个靶标（也是一种miRNA）的调节水平的效果，并评估这些寡核苷酸在组织培养模型中单独或组合使用时的生物学效应与伤口愈合有关。然后，我们将在小鼠中测试这三种寡核苷酸在正常以及受损（缺血和糖尿病）伤口愈合条件下的体内功效。为了增强体内稳定性并消除任何不良的免疫刺激，所有三种寡核苷酸都将进行化学修饰。此外，还有几种不同的交付方法将评估组织 RNA 在加速伤口闭合方面的功效、对寡核苷酸靶标以及伤口愈合涉及的下游因素的影响。这种调节伤口愈合相关因素的新颖的三管齐下的方法可能代表一种治疗慢性伤口的有效策略，也可能是治疗急性伤口的有效策略。