Molecular mechanism of organ remodeling : Gene transcription and cell-cell interaction in mesenchymal

外部应激激活局部间充质细胞（如成纤维细胞和平滑肌细胞）和炎症细胞。这些细胞之间的相互作用促进纤维化、器官肥大和结构重塑。这些变化会影响器官的功能，导致器官衰竭，包括心力衰竭、肾功能衰竭和肝功能衰竭。因此，阐明组织重塑的分子机制将有助于开发新的治疗策略来保护正常器官功能。我们发现了一种kruppel样锌指转录因子BTEB2，它对动脉粥样硬化、血管成形术后再狭窄、组织纤维化和心脏肥厚很重要。我们还发现衰老相关因子Klotho抑制心血管系统的组织重塑。在这个研究项目中，我们分析了控制组织重塑的转录调控和信号转导。该项目的目标是：1)阐明组织重塑中参与间充质细胞活化的转录因子网络；2)阐明Klotho因子在心血管系统中抗应激保护作用的信号转导机制；3)靶向对重塑有重要作用的转录因子和体液因子的药物开发。我们证明了KLF5在心血管和代谢系统的应激反应中发挥重要作用。KLF5与转录因子（如PPARγ和RARα）、辅助因子（如p300）和凋亡相关基因（如PARP）相互作用，控制应激反应并介导组织重塑。为了开发针对KLF5分子网络的新疗法，我们发现一种合成的类维甲酸Am80破坏了KLF5和RARα之间的相互作用，抑制了KLF5的功能。我们发现Am80抑制新内膜的形成和动脉粥样硬化的发生。我们还证明klotho具有血管保护作用。

External stress activates local cells of the mesenchymal origin (e.g., fibroblasts and smooth muscle cells) and inflammatory cells. Interactions between these cells promote fibrosis, organ hypertrophy, and structural remodeling. These changes affect the function of organs and result in organ failure including heart failure, renal failure, and liver failure. Thus, elucidation of molecular mechanisms underlying the tissue remodeling would lead to development novel therapeutic strategies for protection of normal organ function. We identified a Kruppel-like zinc finger transcription factor BTEB2 that is important for atherosclerosis, restenosis after angioplasty, tissue fibrosis, and cardiac hypertrophy. We also found that the ageing related factor Klotho inhibits tissue remodeling of the cardiovascular system. In this research project, we have analyzed transcriptional regulation and signal transduction that control tissue remodeling. The goals of the project were : 1)elucidation of the transcription factor network involved in activation of mesenchymal cells in tissue remodeling ; 2)elucidation of signal transduction mechanisms involved in the protective function of the Klotho factor against stress in the cardiovascular system ; and 3)development of drugs targeting transcription factors and humoral factors that are important for remodeling. We demonstrated that KLF5 plays essential roles in stress responses in both cardiovascular and metabolic systems. KLF5 interacts with transcription factors, such as PPARγ and RARα, cofactors, such as p300, and apoptosis-related genes, such as PARP to control stress response and to mediate tissue remodeling. To develop novel therapeutics targeting the KLF5 molecular network, we found a synthetic retinoid Am80 disrupts the interaction between KLF5 and RARα and inhibits KLF5's function. We showed that Am80 inhibited neointima formation and atherogenesis. We also demonstrate that klotho exhibits vascular protective effects.