Selection of an anti-ceramide mitigator of acute radiation toxicity of the GI tra

胃肠道急性放射毒性抗神经酰胺缓解剂的选择

基本信息

批准号：
8122867
负责人：
Jim Rotolo
金额：
$ 30万
依托单位：
CERAMIDE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8122867
关键词：
Acute Address Adsorption Affinity American Animal Model Animals Antibodies Apoptosis Apoptotic Autologous Autopsy Binding Biological Assay Bioshield Blood Vessels Bone Marrow Cause of Death Cell Death Cell Survival Cell membrane Ceramides Cessation of life Clinical Commit Complication Data Dehydration Development Diarrhea Disasters Dose Drug Kinetics Electrolytes Endothelium Enzyme-Linked Immunosorbent Assay Event Functional disorder Gastrointestinal tract structure General Population Generations Goals Hematopoietic stem cells Hour Human IgG1 Immune Immunoglobulin Fragments Immunoglobulin M Injury Intestinal Mucosa Intestines Ionizing radiation Lamina Propria Marrow Mediating Medical Membrane Membrane Lipids Modeling Monitor Monoclonal Antibodies Mus National Institute of Allergy and Infectious Disease Nuclear Nuclear Accidents Nutrient Pathology Pharmacodynamics Phase Production Protocols documentation Radiation Radiation Syndromes Radiation Toxicity Radiobiology Reagent Recovery Regression Analysis Research Research Proposals Schedule Screening procedure Sepsis Small Business Innovation Research Grant Soil Sphingolipids Stem cell transplant Stem cells Syndrome Therapeutic Thin Layer Chromatography Time Tissues Toxic effect Translating Treatment-Related Cancer United States Dept. of Health and Human Services Villus Whole-Body Irradiation base chemotherapy effective therapy gastrointestinal gastrointestinal epithelium improved in vivo interest intestinal crypt irradiation novel organ regeneration pre-clinical prevent product development programs research study

项目摘要

DESCRIPTION (provided by applicant): The Gastrointestinal (GI) Syndrome is a primary complication of cancer treatments, associated with delivery of therapeutic doses of chemotherapy and radiation, and also constitutes a potentially lethal result of accidental ionizing radiation (IR) exposure. The syndrome results from depletion of the stem cell compartment of the GI tract, resulting in denudation of the GI epithelium, and death due to lack of nutrient adsorption, diarrhea and dehydration, electrolyte imbalance and enterobacterial sepsis. There is no effective approach to mitigate the basic underlying pathology of the GI Syndrome. The Project BioShield Act, part of a strategy to defend American soil from threat of a limited nuclear attack or nuclear accident, emphasizes the need for research towards development of effective countermeasures to mitigate GI tract lethality in the general population at least 24 h after radiation exposure. Evidence that microvascular dysfunction within the crypt-villus unit regulates GI tract lethality identified a novel target for mitigation of the GI Syndrome. This vascular dysfunction, mediated by generation of the pro-apoptotic sphingolipid ceramide on the outer leaflet of the endothelial plasma membrane and subsequent ceramide-driven membrane reorganization into ceramide-rich platforms (CRPs), is amenable to pharmacologic inactivation. Based upon these discoveries, mouse 2A2 (m2A2) anti- ceramide IgM antibody was developed to bind and neutralize ceramide, and inhibit IR-induced tissue damage in vivo. m2A2 significantly improved GI tract stem cell survival and promoted tissue recovery, both when administered prior to or up to 24 hours following lethal radiation exposure. Critically, 2A2 mitigated both sublethal and lethal GI tract damage. These data indicate that anti-ceramide Abs represent a novel class of pharmacologic agents for mitigation of the GI Syndrome, and for use as radiological countermeasures. Humanized 2A2 has since been generated, and confirmed to be an effective mitigator of crypt lethality. In the current application, we propose to identify the most promising radiation mitigating therapeutic from a panel of humanized anti-ceramide reagents, including anti-ceramide Abs and antibody fragments, for advancement into preclinical development. PUBLIC HEALTH RELEVANCE: The Department of Health and Human Services has emphasized the need for radiation biology research towards development of effective countermeasures to mitigate gastrointestinal (GI) tract lethality in the general population at least 24 h after radiation exposure. Recent evidence demonstrates that neutralization of the membrane lipid ceramide with a monoclonal antibody specific for ceramide protects GI stem cells from death and promotes organ regeneration following high-dose radiation exposure, even when administered 24 hours following exposure. This research proposal aims to identify the most effective radiation mitigator from a panel of humanized anti-ceramide reagents for advancement into preclinical development.

描述（由申请人提供）：胃肠道（GI）综合症是癌症治疗的主要并发症，与治疗剂量的化疗和放疗有关，并且还构成意外电离辐射（IR）暴露的潜在致命结果。该综合征是由于胃肠道干细胞室耗竭，导致胃肠道上皮剥脱，并因缺乏营养吸收、腹泻和脱水、电解质失衡和肠杆菌败血症而死亡。没有有效的方法来减轻胃肠道综合症的基本病理学。《生物盾计划法案》是保护美国土壤免受有限核攻击或核事故威胁的战略的一部分，强调需要研究制定有效的对策，以减轻辐射暴露后至少 24 小时内普通人群胃肠道的致命性。隐窝绒毛单位内的微血管功能障碍调节胃肠道致死率的证据确定了缓解胃肠道综合症的新目标。这种血管功能障碍是由内皮质膜外叶上促凋亡鞘脂神经酰胺的生成以及随后神经酰胺驱动的膜重组为富含神经酰胺的平台（CRP）介导的，易于药理学失活。基于这些发现，开发了小鼠 2A2 (m2A2) 抗神经酰胺 IgM 抗体来结合和中和神经酰胺，并抑制体内 IR 诱导的组织损伤。 m2A2 在致命辐射暴露之前或之后 24 小时内施用，可显着提高胃肠道干细胞存活率并促进组织恢复。至关重要的是，2A2 减轻了亚致死和致死的胃肠道损伤。这些数据表明，抗神经酰胺抗体代表了一类新型药物，用于缓解胃肠道综合症，并用作放射对策。人源化 2A2 现已生成，并被证实是隐窝致死性的有效缓解剂。在当前的应用中，我们建议从一组人源化抗神经酰胺试剂（包括抗神经酰胺抗体和抗体片段）中确定最有前途的放射缓解治疗方法，以推进临床前开发。公共卫生相关性：卫生与公众服务部强调需要进行辐射生物学研究，以制定有效的对策，以减轻普通人群在辐射暴露后至少 24 小时内胃肠道 (GI) 的致死率。最近的证据表明，用神经酰胺特异性单克隆抗体中和膜脂神经酰胺可以保护胃肠道干细胞免于死亡，并促进高剂量辐射暴露后的器官再生，即使在暴露后 24 小时内施用也是如此。该研究提案旨在从一组人源化抗神经酰胺试剂中找出最有效的辐射缓解剂，以推进临床前开发。