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.

项目概要/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大健康负担。确定调节细胞功能的基本分子信号，并将研究结果转化为利用动物模型研究疾病的发病机制，从而确定新的分子靶点和治疗策略疾病的预防和干预。我们一直在进行癌症发病机制和治疗耐药性的转化研究。重点研究死亡受体信号通路在调节癌细胞凋亡中的作用及其作用我们的研究表明，调节死亡- 诱导信号复合物（DISC）决定下游的存活和凋亡信号。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 (PARP1)，导致胰腺癌对治疗产生耐药性，这是有效癌症治疗的一个关键障碍。基于这一新颖的发现，我们当前的 VA 绩效评审奖（2014-2018 年）旨在描述机制 DISC相关的PARP1在调节胰腺癌对抗体免疫疗法的抵抗中发挥着重要作用我将继续与人源化抗死亡受体5抗体（TRA-8/CS1008）进行长期合作。 VA 医师科学家 Jay M McDonald 医学博士（弗吉尼亚州伯明翰病理学）和 TRA-8/CS1008 的发明者， Tong Zhou，医学博士（医学，UAB）。CS1008疗法在某些癌症的临床试验中是有效的，但在包括胰腺肿瘤在内的其他肿瘤中具有耐药性，我们研究的首要目标是阐明分子机制并鉴定使胰腺癌对 TRA-8 诱导敏感的新化合物细胞凋亡，从而克服耐药性并导致成功的治疗。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）的表型可塑性提供了一个很好的模型来研究我们特别感兴趣的是研究 VSMC 的作用。使用组织特异性基因敲除小鼠模型，我们获得了骨样细胞（血管钙化）。成骨转录因子 Runx2 在调节血管钙化中发挥重要作用，我们发现了动脉粥样硬化、糖尿病和终末期肾病的新机制。氧化应激增加和高血糖导致脉管系统中 Runx2 的潜在上调。还发现了 VSMC、巨噬细胞和血管干细胞在发育过程中的一种新的串扰我们发表了一系列研究成果，证明了动脉粥样硬化钙化的关键综合作用。 Runx2在VSMC中的上调促进血管病理的作用已得到高度认可和引用。我们的首要目标是确定调节血管钙化发病机制的新机制我们聚集了伯明翰退伍军人管理局的几位医学科学家。包括 Paul Sanders 博士和 Anupam Agarwal 博士（肾脏病学）以及 Louis Dell'Italia 博士（心脏病学和我们的合作研究导致了一个计划项目的开发，以研究“血管疾病的新型调节剂”，该项目得到了 VA 的支持（2012-2016 年）。这些研究不仅将阐明潜在的基本分子机制调控癌症耐药性和血管疾病的发病机制，同时也提供新的分子见解有助于进一步研究，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。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TLR4 regulates pulmonary vascular homeostasis and remodeling via redox signaling.

TLR4 通过氧化还原信号调节肺血管稳态和重塑。

DOI：
发表时间：
2016
期刊：
影响因子：
0
作者：
Ma, Liping;Ambalavanan, Namasivayam;Liu, Hui;Sun, Yong;Jhala, Nirag;Bradley, Wayne E;Dell'Italia, Louis J;Michalek, Sue;Wu, Hui;Steele, Chad;Benza, Raymond L;Chen, Yabing
通讯作者：
Chen, Yabing

Epsins in vascular development, function and disease.

epsins 在血管发育、功能和疾病中的作用。