TNF-α在下丘脑室旁核参与糖尿病性ED及性行为障碍发病机制的研究

我们以往的研究结果表明，促炎性细胞因子TNF-α，在阴茎组织中通过下调平滑肌舒张，参与了糖尿病性勃起功能障碍（ED）的发病机制。在本项目的预实验中，我们进一步发现，TNF-α还可能在中枢水平，即下丘脑室旁核（PVN）内，参与糖尿病性ED的发生和发展。在此基础上，我们提出以下新科学假说：TNF-α作为重要的致病因子，可能在中枢（下丘脑PVN）和外周（阴茎组织）两个不同层面发挥协同作用，形成一个促进糖尿病性ED及相关性行为障碍发生和发展的独特病理体系。围绕这一假说，本项目拟从整体、细胞与分子水平，应用中枢靶向干预、机能学、行为学和分子生物学实验技术，在2型糖尿病大鼠模型中，研究TNF-α在PVN的表达特征、TNF-α对神经元功能的影响及其路径与机制，以及TNF-α在中枢和外周参与糖尿病性ED发病的协同作用。实验结果将从新的视角阐释糖尿病性ED及性行为障碍复杂的发病机理，为临床治疗提供新靶点。

Previous studies have shown that neurohumoral alterations within the hypothalamic paraventricular nucleus (PVN) might contribute to the diabetes-associated erectile dysfunction (ED) and the blunted sexual behavior. The precise central pathophysiological mechanisms of diabetes-associated ED remain unknown. ..Our laboratory has carried out series of experiments documenting the role of TNF-α in diabetes-associated ED. Our recent results suggest that diabetes-associated increase in TNF-α expression promotes the development of ED by stimulating the production of NADPH oxidase-derived ROS in the corpus cavernosum. We found in our preliminary studies that the local expression of TNF-α within the PVN was up-regulated and closely associated with the decline of nNOS expression in high-fat diet/STZ induced type 2 diabetic rats. In addition, we demonstrated that TNF-α modulated the neurotransmitters in the PVN and contributed to increased sympathoexcitation in heart failure. ..Thus, we hypothesize that up-regulation of TNF-α within the hypothalamic PVN is involved in the central functional alterations leading to the diabetes-associated ED and sexual behavior disorders. ..To test our hypothesis, we seek to identify the central effects of increased TNF-α on neurohumoral functions of the PVN in type 2 diabetic rats displaying ED and sexual behavior disorders, using a CNS-targeting technology in vivo. The potential regulatory molecules and signaling pathways will be examined in vivo and in vitro. The possible synergistic effects of central and peripheral TNF-α will also be investigated in this study. Our study is designed to unveil new mechanisms by which TNF-α within the hypothalamic PVN plays a role in the pathogenesis of diabetes-associated ED and to provide a novel target for clinical therapy.