T1DM免疫调节肽P277功能优化及诱发AS副作用的逆向调控

动脉粥样硬化是糖尿病的重要并发症和致死原因。具有抗动脉粥样硬化和抗糖尿病双功能蛋白将成为理想的抗糖尿病药物。我们在一项结题的国家自然科学青年基金项目中，尝试对HSP65 分子进行定向改造，保留其抗动脉粥样硬化功效、强化其抗糖尿病功效。我们将P277肽重复串联并融合于HSP65羧基端构建的融合蛋白HSP65-6×P277经粘膜免疫NOD小鼠时，可减轻1型糖尿病的临床症状, 且效果优于单独使用P277。但在后续研究中发现HSP65-6×P277经粘膜却能诱发动脉粥样硬化。经进一步研究发现诱发动脉粥样硬化的毒性表位为P277肽N端的B表位。本申请旨在遴选安全表位，通过表位替换的方式，构建新型P277肽疫苗。在优化P277肽原有抗糖尿病作用的同时，消除其诱发动脉粥样硬化的副作用。

Atherosclerosis is a major complication of diabetes. Thus, end stage diabetic patients require a vaccine therapy that will not only treat their type I diabetes but also treat atherosclerosis. P277 (trade name DiaPep277) is a vaccine used to treat type I diabetes and is currently tested in phase III clinical trial. We have read and confirmed that heat shock protein 65 (Hsp65) can cure atherosclerosis. Our team has produced a construct using linear repeats of the P277 peptide fused to the C-terminal region of HSP65 that should cure both atherosclerosis and type I diabetes. However, we found that when the construct is administered by nasal, vascular endothelial cells are injured and atherosclerosis is induced. We tested different regions of the P277 peptide and found that the B epitope （N-Terminal）induces atherosclerosis. The purpose of this project is to artificially regulate the P277 peptide by replacing the atherosclerosis-causing B epitope with a mutant that will not cause atherosclerosis nor reduce the ability to cure type I diabetes. Based on this new construct, we should be able to make P277 a more effective medicine by enhancing its effectiveness in controlling diabetes and eliminating the induction of atherosclerosis.