High Gulcose Promotes Myocyte Apoptosis by PKC Pathways

高葡萄糖通过 PKC 途径促进心肌细胞凋亡

基本信息

批准号：
7452405
负责人：
ashwani malhotra
金额：
$ 33.17万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7452405
关键词：
Adult Antioxidants Apoptosis Apoptotic Area Attenuated Bad protein Biochemical Biological Biological Assay Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Count Cell Death Cell Survival Cellular biology Complement Condition Coupling Cytoprotection Data Deterioration Development Diabetes Mellitus Electron Transport Electrons Essential Genes Exhibits Failure Family Generations Genes Genetically Engineered Mouse Genotype Heart Hyperglycemia In Vitro Intervention Investigation Isoenzymes Laboratories Left Left Ventricular Dysfunction Mediating Mediator of activation protein Mitochondria Mitochondrial Proteins Modeling Molecular Muscle Cells Myocardium Null Lymphocytes Organ Oxidative Stress Pathway interactions Peptides Phenotype Physiological Pore Proteins Primary Myocardial Diseases Protein Kinase C Proteins Protocols documentation Pump RNA Rattus Reactive Oxygen Species Resistance Risk Factors Role Signal Transduction Signaling Molecule Source Streptozocin Superoxides Thioredoxin Translations VDAC1 gene Ventricular Ventricular Remodeling Voltage-Dependent_Anion_Channel-1 base cytochrome c diabetic hemodynamics in vivo inhibitor/antagonist loss of function novel novel strategies prevent programs protein kinase C epsilon reactive oxygen intermediate receptors for activated C kinase response

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus (DM) is a major risk factor for the development of cardiovascular disease. The myocardium is a target for hyperglycemia induced oxidative stress, which leads to myocyte cell death by apoptosis and left ventricular (LV) dysfunction. An emerging area of cell biology is the application of gene based strategies to inhibit programmed cell death. The global objective of this approach is to preserve or restore cell number and to prevent or attenuate remodeling. Exciting new data from our laboratory demonstrated PKC epsilon dependent cardioprotection against the hyperglycemia apoptosis signal. An important question concerns the translation of in vitro cytoprotection assays to the in vivo condition of the diabetic myocardium. Specific Aims 1 and 2 will explore this question in the streptozotocin (STZ) DM model, in 2 strains of genetically engineered mice, with cardiac specific expression of PKC epsilon activator (pseudo epsilon-RACK) or a PKC epsilon inhibitor (eV1). Immunocytochemical, biochemical and physiological approaches will be performed to identify the molecular components of the survival program and which genes are essential for PKC epsilon dependent cardioprotection. Under Specific Aim 3, the novel strategy of short interfering RNA (siRNA) will be employed to induce stable loss of function genotypes in primary cultures of adult rat ventricular myocytes (ARVM). The objective will be to identify which of the PKC epsilon signaling molecules are essential for the expression of the survival phenotype. These studies will complement those outlined under Specific Aims 1and 2, as selective peptide activators and inhibitors of PKC epsilon will be delivered to ARVM-null cells maintained under hyperglycemic conditions. We will also explore the role of hyperglycemia induced oxidativestress in the modulation of the PKC epsilon survival signal. Antisense inhibition of the antioxidant protein, thioredoxin in ARVM, followed by delivery of PKC epsilon activators or inhibitors will be the approach used here. The proposed investigations are novel and fundamental to the development of gene based therapy to inhibit myocyte apoptosis in the diabetic heart.

描述（由申请人提供）：糖尿病（DM）是心血管疾病发展的主要危险因素。心肌是高血糖诱导氧化应激的靶标，这会导致凋亡和左心室（LV）功能障碍导致心肌细胞死亡。细胞生物学的新兴领域是基于基因的策略抑制程序性细胞死亡的应用。这种方法的全球目标是保留或恢复细胞数，预防或衰减重塑。来自我们实验室的令人兴奋的新数据表明，针对高血糖凋亡信号的PKC Epsilon依赖性心脏保护。一个重要的问题是将体外细胞保护测定法转换为糖尿病心肌体内状况。具体目的1和2将在2种基因工程小鼠菌株的链蛋白酶（STZ）DM模型中探索这个问题，并具有PKC Epsilon激活剂（Pseudo Epsilon-Rack）或PKC Epsilon抑制剂的心脏特异性表达（EV1）。将采用免疫细胞化学，生化和生理方法来识别生存程序的分子成分，哪些基因对于PKC Epsilon依赖性心脏保护至关重要。在特定的目标3下，将采用短暂干扰RNA（siRNA）的新型策略来诱导成年大鼠心室肌细胞（ARVM）的原发性培养物中稳定的功能基因型丧失。目的是确定哪种PKC Epsilon信号分子对于表达生存表型至关重要。这些研究将补充特定目的1和2下概述的研究，因为选择性肽激活剂和PKC Epsilon的抑制剂将递送至在高血糖条件下维持的ARVM-NULL细胞。我们还将探讨高血糖诱导的氧化毒素在PKC Epsilon存活信号调节中的作用。反义抑制抗氧化剂蛋白，ARVM中的硫氧还蛋白，然后递送PKC Epsilon激活剂或抑制剂，将是此处使用的方法。拟议的研究是新颖的，是基于基因疗法的发展，以抑制糖尿病心脏的肌细胞凋亡。