血管形成与稳态维持的分子机理与新颖药物设计

Angiogenesis is essential in embryonic development, normal growth, and tissue regeneration. It is a multi-step process and is regulated by an elaborated molecular network. Dysregulation of angiogenesis associates with cancer, inflammation and vascular diseases. Although drugs targeting angiogenesis have been applied in the treatment of various human diseases, the drug resistance is still an obstacle in these applications. All these together necessitate a clear understanding of the molecular basis for angiogenesis and the development of novel target therapeutics. Mounting evidences reveal that bone morphogenetic proteins (BMPs) play an emerging, pivotal role in vascular development and angiogenesis. For example, mutations in the BMP9 and its receptors, Endoglin and Activin-Like Receptor Kinase 1 (ALK1), cause abnormal vasculature in Hereditary Hemorrhagic Telangiectasia (HHT) patients. Our early structural work determined the molecular mechanism for BMP9 activation from its secreted pro-protein complex. This proposal aims to address the following open questions: How is BMP9 recognized by its receptor Endoglin? And how does the Endoglin/ALK1 complex mediate BMP9 transmembrane signaling? Based on the understanding of these questions, we will develop novel therapeutic drugs and probes targeting angiogenesis. In addition, we will exploit the potentials of these agents in the treatment of cancer and vascular diseases.

血管稳态与重构对于机体的发育、生长、创伤修复、组织再生都起着重要作用，而其失调直接导致了癌症、炎症、及心脑血管等疾病。因此深入理解与研究新的调控血管重构与稳态维持的信号通路及其分子机理，阐明关键节点分子的结构与功能，并在此基础上开发新的靶向药物与治疗策略，不论在基础生物学还是临床医学上都有着非常重大的意义。成骨蛋白BMP9是近来发现的调控血管形成与稳态的重要发育信号分子。我们在解析其前体复合物结构的基础上，将进一步应用晶体学、脂纳米盘重组与冷冻电镜研究它与受体Endoglin的识别机理及相应跨膜复合物结构。以此为基础，我们将进行新颖的靶向性药物与探针设计，并探讨其在治疗癌症和血管类疾病中的潜在应用。

血管形成与稳态维持不仅在发育与组织损伤修复中起着不可或缺的作用，且直接和心血管、癌症、炎症等重大疾病密切相关。研究血管形成与稳态维持的分子机理，阐明新的通路及其关键节点分子的结构与功能关系，并在此基础上开发新的靶向药物与治疗策略，具有重要的科学意义。在基金委的资助下，我们研究了上述科学问题，并取得了如下进展：.1）.我们研究了BMP9活性调节的分子机理，发现BMP9在其生物合成中所形成的不同剪切体不仅在生物活性上存在显著差异，而且不同的剪切体之间还存在相互拮抗作用，这一发现为理清BMP9参与血管形成与稳态维持的复杂机理、开发相关靶向药物奠定了基础。.2）.我们研究了Endoglin识别BMP9前后的构象变化，计算了Endoglin ZpN 结构域在无BMP9结合时的二聚体结构模型，研究了其生物学功能。.3）.通过分析、比较BMP9与PDGF-D的结构，探究了PDGF-D的激活与抑制机理，发现PDGF-D的前体结构域对血管形成中起重要调节作用的PDGF-B、PDGF-D具有交叉抑制功能，为相关蛋白药物的研发奠定了基础。