Endogenous sphingosine-1-phosphate as a radioprotector of intestinal tissues

内源性 1-磷酸鞘氨醇作为肠道组织的辐射保护剂

基本信息

批准号：
8010757
负责人：
JULIE D SABA
金额：
$ 10万
依托单位：
CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-05 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8010757
关键词：
Address Animals Apoptosis Apoptotic Attenuated Autologous Bone Marrow Transplantation Bacterial Infections Biochemical Biological Assay Biology Bone Marrow Transplantation Cell Death Cell Survival Cells Ceramides Chemistry Clinical Collaborations Color Consultations Cytotoxic Chemotherapy DNA Damage Data Development Dose Drug Kinetics Endothelial Cells Enzymatic Biochemistry Enzymes Epithelial Evaluation Event FDA approved Food Food Additives Gastrointestinal Injury General Population Genetic Harvest Hematopoietic Stem Cell Transplantation Human Imidazole In Vitro Inflammation Inflammatory Injury International Intervention Intestinal Mucosa Intestines Intravenous Ionizing radiation Kinetics Laboratories Legal patent Lethal Dose 50 Licensure Lipids Lyase Measurement Molecular Molecular Analysis Mus National Institute of Allergy and Infectious Disease Natural regeneration Oral Oral Administration Organ Ovary Paris, France Pathology Pathway interactions Pharmaceutical Preparations Pharmacology Plasma Positioning Attribute Preparation Prevention Radiation Radiation Enteritis Radiation Induced DNA Damage Radiation Injuries Radiation-Protective Agents Radiobiology Radioprotection Recovery Regimen Research Rodent Role Route Safety Signal Pathway Signal Transduction Sphingolipids Sphingomyelinase Staging Sterility Stress Technology Terrorism Testing Time Tissues Toxic effect Toxicology Wild Type Mouse analog angiogenesis animal tissue base cancer cell caramel cell injury colonic crypt cytokine drug development experience gastrointestinal improved in vivo indexing inhibitor/antagonist interest intestinal villi irradiation novel prevent product development prophylactic radiation effect research study response small molecule sphingosine 1-phosphate subcutaneous

项目摘要

DESCRIPTION (provided by applicant): Ceramide and sphingosine-1-phosphate (S1P) are bioactive lipids that regulate cell survival through activation of specific signaling pathways. Ceramide accumulates in cells in response to radiation and activates apoptosis pathways. Inhibiting ceramide synthesis protects against radiation injury. In contrast, the ceramide metabolite S1 P promotes cell survival in response to stress and is essential for angiogenesis. S1 P antagonizes apoptotic pathways including those induced by ceramide and radiation. Importantly, S1P prevents radiation-induced apoptosis and sterility in mice. Thus, while ceramide contributes to radiation enteritis, its conversion to S1P provides an internal fine-tuning signal that limits the intensity of radiation responses. Our preliminary studies indicate that S1P is a potent radioprotectant of the gut, promoting cell, tissue and animal survival after lethal doses of radiation. However, S1P is difficult to deliver. Thus, we have devised an alternative approach to raise intracellular levels of S1P and achieve radioprotection. S1P is catabolized by the enzyme S1 P lyase (SPL). SPL is highly expressed in intestinal villi and colonic crypts, where it maintains low S1 P levels, promoting cell turnover. SPL expression is induced by DNA damage and radiation in vitro and in vivo, and SPL expression promotes radiation-induced apoptosis, whereas SPL inhibition attenuates apoptosis after DNA damage. Tetrahydroxybutyl-imidazole (THI), a small molecule constituent of caramel food coloring, was recently found to be an SPL inhibitor. We show that oral administration of THI to mice reduces SPL activity and elevates S1P levels in colonic and intestinal tissues. Based on these findings and the observed radioprotective effect of S1 P in mice, we hypothesize that THI provides a safe means of achieving radioprotection in the gut and other tissues by rapidly inhibiting SPL activity and elevating intracellular and circulating levels of the endogenous radioprotectant, S1 P. To address this possibility, we have proposed three integrated specific aims: 1) To define the kinetics and dose requirements needed for THI to raise tissue and circulating S1 P levels; 2) To evaluate the pre- and post-expo-sure efficacy of THI as a protector of radiation-induced intestinal pathology; 3) To assess whether THI administration can prolong survival after radiation exposure. THI is an ideal candidate radioprotective agent due to its ease of delivery, minimal associated toxicity profile, and potential for rapid product development and multi-organ radioprotection.

描述（由申请人提供）：神经酰胺和1-磷酸盐（S1P）是生物活性脂质，可通过激活特定信号通路来调节细胞存活。神经酰胺响应辐射响应细胞积聚并激活凋亡途径。抑制神经酰胺的合成可预防辐射损伤。相比之下，神经酰胺代谢物S1 P促进了响应胁迫的细胞存活，对于血管生成至关重要。 S1 P拮抗凋亡途径，包括神经酰胺和辐射诱导的途径。重要的是，S1P可防止辐射诱导的小鼠凋亡和无菌性。因此，虽然神经酰胺有助于辐射肠炎，但其转化为S1P提供了一个内部微调信号，从而限制了辐射反应的强度。我们的初步研究表明，S1P是肠道的有效放射保护剂，可在致命的辐射剂量后促进细胞，组织和动物生存。但是，S1P很难交付。因此，我们设计了一种替代方法来提高细胞内水平的S1P并实现辐射保护。 S1P被酶S1 P裂解酶（SPL）分解代谢。 SPL在肠绒毛和结肠隐窝中高度表达，在该隐窝中保持较低的S1 P水平，从而促进细胞更新。 SPL表达是由DNA损伤和体外和体内辐射诱导的，SPL表达促进了辐射诱导的细胞凋亡，而SPL抑制作用会减弱DNA损伤后的凋亡。焦糖食品着色的小分子组成的小分子，最近被发现是SPL抑制剂。我们表明，对小鼠的口服给药可降低SPL活性，并提高结肠和肠道组织中的S1P水平。基于这些发现以及S1 P在小鼠中观察到的放射保护作用，我们假设这提供了一种安全的方法，可以通过快速抑制SPL的活性并升高细胞内和循环水平来实现肠道和其他组织中的放射性保护，以使这种可能性的固定性固定为1：1的范围，我们已经伸出了三个范围。这需要提高组织和循环S1 P水平； 2）评估THI作为辐射诱导的肠道病理的保护因子的前和后释放功效； 3）评估该辐射暴露后是否可以延长给药。 THI是理想的候选辐射保护剂，因为其易于递送，最小相关的毒性概况以及快速产物开发和多器官辐射保护的潜力。