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-磷酸鞘氨醇 (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。神经酰胺响应辐射而在细胞中积聚并激活细胞凋亡途径。抑制神经酰胺合成可防止辐射损伤。相比之下，神经酰胺代谢物 S1 P 可以促进细胞应对应激的存活，并且对于血管生成至关重要。 S1 P 拮抗细胞凋亡途径，包括神经酰胺和辐射诱导的细胞凋亡途径。重要的是，S1P 可以防止辐射诱导的小鼠细胞凋亡和不育。因此，虽然神经酰胺会导致放射性肠炎，但它向 S1P 的转化提供了内部微调信号，限制了辐射反应的强度。我们的初步研究表明，S1P 是一种有效的肠道辐射防护剂，可在致命剂量的辐射后促进细胞、组织和动物的存活。然而，S1P很难交付。因此，我们设计了一种替代方法来提高细胞内 S1P 水平并实现辐射防护。 S1P 由 S1P 裂解酶 (SPL) 分解代谢。 SPL 在肠绒毛和结肠隐窝中高表达，维持较低的 S1 P 水平，促进细胞更新。 SPL 表达在体外和体内由 DNA 损伤和辐射诱导，SPL 表达促进辐射诱导的细胞凋亡，而 SPL 抑制则减弱 DNA 损伤后的细胞凋亡。四羟基丁基咪唑 (THI) 是焦糖食用色素的一种小分子成分，最近被发现是一种 SPL 抑制剂。我们发现，给小鼠口服 THI 会降低结肠和肠道组织中的 SPL 活性并提高 S1P 水平。基于这些发现以及在小鼠中观察到的 S1 P 的辐射防护作用，我们假设 THI 提供了一种安全的方法，通过快速抑制 SPL 活性并提高内源性辐射防护剂 S1 P 的细胞内和循环水平，在肠道和其他组织中实现辐射防护。为了解决这种可能性，我们提出了三个综合的具体目标：1）确定 THI 提高组织和循环 S1 P 水平所需的动力学和剂量要求； 2) 评估 THI 作为辐射诱发肠道病理保护剂的暴露前和暴露后功效； 3) 评估THI给药是否可以延长辐射暴露后的生存期。 THI 是一种理想的候选辐射防护剂，因为它易于递送、相关毒性极小，并且具有快速产品开发和多器官辐射防护的潜力。