BLR&D Research Career Scientist Award Application

项目总结/摘要 我的主要研究兴趣是了解基因调控和功能的分子机制， 癌症和心血管疾病的发病机制，这是我们退伍军人的两个主要健康负担。我们寻求 确定调节细胞功能的基本分子信号，并将研究结果转化为 使用动物模型研究疾病的发病机制，以便确定新的分子靶点和治疗策略。 疾病的预防和干预。 癌症发病机制和耐药性转化研究。我们一直 重点关注死亡受体信号通路在调节癌细胞凋亡中的作用， 癌症肿瘤发生和对治疗的抗性。我们的研究表明，调节死亡- 诱导信号复合物（DISC）决定下游的存活和凋亡信号。最近我们 在死亡受体-5 DISC中发现了一种新的调节因子，聚（ADP-核糖）聚合酶1（PARP 1）， 导致胰腺癌对治疗的抗性，这是有效癌症治疗的关键障碍。 基于这一新的发现，我们目前的VA优点审查奖（2014-2018）是为了描述机制， 潜在的DISC相关PARP 1在调节胰腺癌对抗体免疫疗法的抗性中的作用 人源化抗死亡受体5抗体（TRA-8/CS1008）。我将继续与 VA医师科学家，Jay M McDonald，MD（病理学，Birmingham VA）和TRA-8/CS1008的发明者， Tong Zhou，MD（Medicine，UAB）.由于CS1008疗法在一些癌症的临床试验中是有效的， 在包括胰腺肿瘤在内的其他肿瘤中耐药，我们研究的首要目标是阐明 分子机制，并确定新的化合物，敏感胰腺癌TRA-8诱导 细胞凋亡，从而克服耐药性，导致成功的治疗。 血管疾病中血管平滑肌细胞的分化和重编程。 血管平滑肌细胞（VSMC）的表型可塑性为研究血管平滑肌细胞的表型可塑性提供了一个很好的模型。 细胞分化在健康和疾病中的作用。我们特别感兴趣的是研究VSMC 变成骨样细胞（血管钙化）。使用组织特异性基因敲除小鼠模型， 证实了成骨转录因子Runx 2在调节血管钙化中的重要作用， 动脉粥样硬化、糖尿病和终末期肾病的特征。我们发现了新的机制 通过增加的氧化应激和高血糖导致血管系统中潜在的Runx 2上调。我们有 还发现了VSMC，巨噬细胞和血管干细胞之间的一种新的串扰， 动脉粥样硬化钙化我们已经发表了一系列工作，展示了 Runx 2在VSMC中的上调促进了血管病理的发生，这一点已被高度认可和引用。 我们的首要目标是确定调节血管钙化发病机制的新机制 并确定治疗靶点。我们召集了伯明翰退伍军人管理局的几位医生科学家 包括Paul Sanders博士和Anupam Agarwal博士（肾脏科）以及Louis Dell'Italia博士（心脏科和 助理参谋长）。我们的合作研究导致了一个项目的发展， 调查“血管疾病的新型调节剂”，该研究得到了VA的支持（2012-2016）。 这些研究不仅将阐明潜在的基本分子机制， 调节肿瘤耐药和血管疾病的发病机制，也为肿瘤的治疗提供了新的分子基础。 促进进一步研究的见解，将这些发现转化为患者护理的治疗策略， 改善退伍军人的健康、寿命和生活质量。

Project Summary/Abstract My major research interest is to understand molecular mechanisms of gene regulation and function in the pathogenesis of cancer and cardiovascular disease, two major health burdens for our Veterans. We seek to determine the fundamental molecular signals that regulate cellular function, and translate the findings in the pathogenesis of disease using animal models, so as to identify novel molecular targets and strategies for prevention and intervention of disease. Translational research on cancer pathogenesis and resistance to therapy. We have been focused on the death receptor signaling pathways in regulating apoptosis of cancer cells and their roles in cancer tumorigenesis and resistance to therapy. Our studies have demonstrated that modulating the Death- Inducing Signaling Complex (DISC) determines the downstream survival and apoptosis signals. Recently, we discovered a novel regulator, poly(ADP-ribose) polymerase 1 (PARP1), in the death receptor-5 DISC that contribute to the resistance of pancreatic cancer to therapy, a critical hurdle for effective cancer treatment. Based on this novel finding, our current VA merit review award (2014-2018) is to delineate the mechanisms underlying DISC-associated PARP1 in regulating pancreatic cancer resistance to antibody immunotherapy with a humanized anti-death receptor 5 antibody (TRA-8/CS1008). I will continue my long-term collaboration with VA physician scientist, Jay M McDonald, MD (Pathology, Birmingham VA) and the inventor of TRA-8/CS1008, Tong Zhou, MD (Medicine, UAB). As CS1008 therapy has been effective in clinical trials for some cancer but resistant in others including pancreatic tumors, the overarching goal for our investigations is to elucidate the molecular mechanisms and identify new compounds that sensitize pancreatic cancer to TRA-8-induced apoptosis, thus overriding drug resistance and leading to successful therapies. Differentiation and reprogramming of vascular smooth muscle cells in vascular disease. Phenotypic plasticity of vascular smooth muscle cells (VSMC) provides an excellent model to study the function of cell differentiation in health and disease. We are particularly interested in studying how VSMC become bone-like cells (vascular calcification). Using tissue-specific gene knockout mouse models, we have demonstrated an essential role of the osteogenic transcription factor Runx2 in regulating vascular calcification, a feature of atherosclerosis, diabetes and end stage renal disease. We have uncovered novel mechanisms underlying Runx2 upregulation in the vasculature by increased oxidative stress and hyperglycemia. We have also discovered a novel crosstalk between VSMC, macrophages and vascular stem cells in the development of atherosclerotic calcification. We have published a body of work demonstrating a critical integrative role of Runx2 upregulation in VSMC in promoting vascular pathology, which has been highly recognized and cited. Our overarching goals are to identify novel mechanisms that regulate pathogenesis of vascular calcification and identify therapeutic targets. We have brought together several physician scientists at the Birmingham VA including Drs. Paul Sanders and Anupam Agarwal (Nephrology) as well as Dr. Louis Dell'Italia (Cardiology and Associate Chief of Staff). Our collaborative studies have led to the development of a Program Project to investigate “Novel Regulators for Vascular Disease”, which have been supported by the VA (2012-2016). These investigations will not only elucidate the fundamental molecular mechanisms underlying the regulation of cancer drug resistance and pathogenesis of vascular disease, but also provide novel molecular insights facilitating further studies to translate these findings into therapeutic strategies for patient care, so as to improve the Veterans' health, life span and quality of life.