BLR&D Research Career Scientist Award Application

BLR

基本信息

批准号：
10047283
负责人：
Yabing Chen
金额：
--
依托单位：
BIRMINGHAM VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-10-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10047283
关键词：
Animal Model Antibodies Antibody Therapy Apoptosis Area Atherosclerosis Award Biology Blood Vessels Cancer Biology Cardiology Cardiovascular Diseases Cell Differentiation process Cell physiology Cells Cessation of life Clinical Trials Collaborations Complex Development Diabetes Mellitus Disease Drug resistance End stage renal failure Gene Expression Regulation Goals Health Health Care Costs Hyperglycemia Intervention Investigation Longevity Malignant Neoplasms Malignant neoplasm of pancreas Medical center Medicine Modeling Molecular Molecular Target Nephrology Oxidative Stress Pathogenesis Pathogenicity Pathology Patient Care Phenotype Physicians Poly(ADP-ribose) Polymerases Prevention strategy Publishing Quality of life Receptor Signaling Regulation Research Resistance Role Scientist Signal Pathway Signal Transduction Smooth Muscle Myocytes TNFRSF10B gene Therapeutic Tissues Translating Translational Research Up-Regulation Vascular Diseases Vascular Smooth Muscle Vascular calcification Veterans antibody immunotherapy arterial stiffness base bone calcification cancer cell cancer drug resistance cancer therapy career gene function improved insight interest knockout gene macrophage military veteran mouse model novel osteogenic pancreatic neoplasm programs receptor recruit refractory cancer stem cells therapeutic target therapy resistant transcription factor tumorigenesis

项目摘要

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.

项目摘要/摘要我的主要研究兴趣是了解基因调节的分子机制和功能癌症和心血管疾病的发病机理，这是我们退伍军人的两个主要健康烧伤。我们寻找确定调节细胞功能的基本分子信号，并将其转化使用动物模型对疾病的发病机理，以确定新的分子靶标和策略疾病的预防和干预。癌症发病机理和对治疗的抗性的转化研究。我们去过专注于死亡受体信号传导途径，以减轻癌细胞凋亡及其在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（DIS）决定了下游的存活率和凋亡信号。最近，我们在死亡受体5盘中发现了一个新型调节剂Poly（ADP-核糖）聚合酶1（PARP1），有助于胰腺癌对治疗的抗性，这是有效癌症治疗的关键障碍。基于这一小说的发现，我们当前的VA功绩评论奖（2014-2018）是描述机制在调节性胰腺癌对抗体免疫疗法的抗体性中，基本的椎间盘相关PARP1与人源化抗死亡受体5抗体（TRA-8/CS1008）。我将继续与我的长期合作 VA物理科学家，Jay M McDonald，医学博士（伯明翰伯明翰病理学）和Tra-8/CS1008的发明者，医学博士Tong Zhou（医学，UAB）。因为CS1008治疗在某些癌症的临床试验中有效，但在其他包括胰腺肿瘤在内的抗性，我们调查的总体目标是阐明分子机制并鉴定出对Tra-8诱导的敏感胰腺癌的新化合物细胞凋亡，从而抑制耐药性并导致成功的疗法。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细胞分化在健康和疾病中的功能。我们对研究如何VSMC特别感兴趣成为骨状细胞（血管钙化）。使用组织特异性基因敲除小鼠模型，我们有展示了成骨转录因子Runx2在控制血管钙化中的重要作用，动脉粥样硬化，糖尿病和末期肾脏疾病的特征。我们发现了新的机制通过增加的氧化应激和高血糖，脉管系统中的基本RUNX2上调。我们有还发现了VSMC，巨噬细胞和血管干细胞之间的新型串扰动脉粥样硬化钙化。我们已经发表了一系列作品，展示了在促进血管病理学中，VSMC中的Runx2上调，该病理已被高度认可和引用。我们的总体目标是确定调节血管钙化发病机理的新型机制并确定治疗靶标。我们在弗吉尼亚州伯明翰汇集了几位物理科学家包括Drs。 Paul Sanders和Anupam Agarwal（肾脏病）以及Louis Dell'italia博士（心脏病学和参谋长）。我们的协作研究导致了计划项目的发展研究“血管疾病的新型调节剂”，这是VA（2012-2016）支持的。这些投资不仅将阐明该基本的基本分子机制调节癌症耐药性和血管疾病的发病机理，但也提供了新的分子洞察力促进进一步的研究将这些发现转化为患者护理的治疗策略，以便改善退伍军人的健康，寿命和生活质量。