Animal Models for Studying the Genetics of Hypertension

研究高血压遗传学的动物模型

• 批准号: 9900037
• 负责人: NOBUYO MAEDA
• 金额: $ 73.58万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900037
• 关键词: Advanced Glycosylation End Products; Affect; Age-Months; Albumins; Angiotensin II; Animal Model; Apoptotic; Bacterial Infections; Biogenesis; Blood Pressure; Breeding; Cardiac; Cardiac Myocytes; Cells; Code; Complications of Diabetes Mellitus; Creatinine; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dialysis procedure; Diet; Disease; Dose; Echocardiography; Electron Microscopy; Electrons; Embryo; Female; Fibroblasts; Free Radical Scavengers; Free Radicals; Gastric mucosa; Gene Chips; Gene Expression; Genes; Genetic; Genetic Variation; Genetic study; Glucose; Glycosuria; Grant; Heart; Heart Diseases; Heart failure; House mice; Human; Hydrogen Peroxide; Intrinsic factor; Kidney; Kidney Transplantation; Knowledge; Light; Lipid Peroxides; Measurement; Measures; Messenger RNA; Methods; Mitochondria; Monitor; Mus; Mutation; Neonatal; Organ; Oxidases; Pathway interactions; Peritoneal Macrophages; Physiological; Plasma; Play; Population; Pregnancy Outcome; Preventive; Production; Proteins; Pump; Quality of life; Reactive Oxygen Species; Renal function; Resistance; Risk; Role; Stroke; Superoxide Dismutase; Superoxides; Tamoxifen; Testing; Therapeutic; Thiobarbituric Acid Reactive Substances; Time; Tissues; Variant; Vitamin B 12; Vitamins; Work; absorption; cell motility; cell type; db/db mouse; diabetic; diabetic cardiomyopathy; diabetogenic; expectation; familial hypertension; feeding; genetic risk factor; glycemic control; heart function; high risk; light microscopy; macrophage; male; microorganism; microscopic imaging; mimetics; novel; podocyte; post gamma-globulins; prevent; rho GTP-Binding Proteins; subcutaneous; tempol; urinary; young adult

Diabetes mellitus, an increasingly common disease, can cause diabetic nephropathy (DN) and diabetic cardiomyopathy (DCM), leading often to the need for dialysis and kidney transplantation, and to heart failure or stroke. Current knowledge of genes associated with an increased risk for diabetic complications is very limited. Diabetic complications at present are treated by intense glycemic control and management of end organ damages; specific treatment is lacking. Developing and studying mouse models of diabetes that recapitulate the complications seen in the later stages of human diabetes is a powerful approach to enhance our knowledge of genetic risk factors and can contribute to developing preventive and therapeutic measures. During the past grant period we modified several genes expected to affect blood pressure or cardiac/kidney function to obtain a low expressing form of the chosen gene (L) that could be switched to high (H) globally or in a tissue-specific or time-controlled manner with a tamoxifen-inducible Cre. The most serious effects on cardiac/renal function were observed in male mice that were type1diabetic because they had the Akita mutation in the Ins2 gene and had high expression (H/H) of Elmo1, the gene coding for Engulfment and cell motility protein 1. [Associations of SNPs in the ELMO1 gene with DN have been demonstrated in multiple populations.] Accordingly, Specific Aim (i) will focus on increasing our knowledge of the mechanisms that underlie the harmful effects of high Elmo1 expression on DCM and DN, and Specific Aim (ii) will determine the cell types in which Elmo1 high expression acts in enhancing these diabetic complications. Diabetes increases production of the superoxide anion (O2.), a free radical that generates reactive oxygen species (ROS), and the diabetic Elmo1 H/H and Elmo1 H/+ mice have high levels of plasma TBARS (a measure of ROS). Vitamin B12, a normal body constituent generally regarded as safe by the FDA, is a superoxide dismutase mimic, but its potential for inactivating ROS is normally limited because absorption of B12 from the diet is controlled by the small amount of intrinsic factor secreted by the gastric mucosa. However, our preliminary work shows that feeding B12 at high doses enables absorption of the vitamin by an intrinsic- factor-independent pathway that overcomes this limitation; plasma TBARS are normalized, and DCM is no longer seen in young adult Elmo1 H/H diabetic male mice treated with B12. Accordingly, Specific Aim (iii) will optimize the dose of B12 needed to prevent/correct the DCM and DN in Elmo1 H/H diabetic males, compare it with another SOD mimetic (EUK-34) and with tempol, a free radical scavenger, and will determine whether the vitamin affects resistance to microorganisms. Specific Aim (iv) will determine whether B12 has the same benefits in Elmo1 H/H: Ins2 Akita/+ females, and in db/db Elmo1 H/H mice expected to develop type2 DM.

糖尿病是一种日益常见的疾病，可导致糖尿病肾病 (DN) 和糖尿病 心肌病 (DCM)，通常导致需要透析和肾移植，以及心力衰竭或 中风。目前对与糖尿病并发症风险增加相关的基因的了解非常多 有限的。目前，糖尿病并发症的治疗方法是严格血糖控制和终末期管理。 器官损伤；缺乏特异性治疗。开发和研究糖尿病小鼠模型 概括人类糖尿病后期出现的并发症是增强 我们对遗传风险因素的了解可以有助于制定预防和治疗措施。 在过去的资助期内，我们修改了几个预计会影响血压或心脏/肾脏的基因 功能以获得所选基因的低表达形式（L），该形式可以在全局或局部转换为高表达形式（H） 使用他莫昔芬诱导的 Cre 以组织特异性或时间控制的方式进行。最严重的影响是 在患有 1 型糖尿病的雄性小鼠中观察到心/肾功能，因为它们患有秋田犬 Ins2 基因突变，Elmo1 高表达 (H/H)，Elmo1 是编码吞噬和细胞的基因 运动蛋白 1. [ELMO1 基因中的 S​​NP 与 DN 的关联已在多个研究中得到证实 ] 因此，具体目标 (i) 将侧重于增加我们对以下机制的了解： Elmo1 高表达对 DCM 和 DN 有害影响的基础，具体目标 (ii) 将确定 Elmo1 高表达的细胞类型可增强这些糖尿病并发症。 糖尿病会增加超氧阴离子（O2）的产生，这是一种产生活性氧的自由基 种（ROS），糖尿病 Elmo1 H/H 和 Elmo1 H/+ 小鼠血浆 TBARS 水平较高（a ROS 的测量）。维生素 B12 是一种正常的身体成分，通常被 FDA 认为是安全的。 超氧化物歧化酶模拟物，但其灭活 ROS 的潜力通常是有限的，因为 饮食中的维生素 B12 受胃粘膜分泌的少量内因子控制。然而， 我们的初步工作表明，喂食高剂量的 B12 可以通过内在的吸收维生素 克服这一限制的因素独立途径；血浆 TBARS 已标准化，DCM 未标准化 在接受 B12 治疗的年轻成年 Elmo1 H/H 糖尿病雄性小鼠中观察时间更长。因此，具体目标 (iii) 将 优化 Elmo1 H/H 糖尿病男性预防/纠正 DCM 和 DN 所需的 B12 剂量，进行比较 与另一种 SOD 模拟物 (EUK-34) 和 tempol（一种自由基清除剂）一起使用，将确定是否 维生素影响微生物的抵抗力。具体目标 (iv) 将确定 B12 是否具有相同的 对 Elmo1 H/H: Ins2 Akita/+ 雌性小鼠以及预期发展为 2 型 DM 的 db/db Elmo1 H/H 小鼠有益处。