APOC3 mediated dyslipidemia in diabetic kidney disease and atherosclerosis

APOC3 介导的糖尿病肾病和动脉粥样硬化中的血脂异常

• 批准号: 10580375
• 负责人: Jenny E. Kanter
• 金额: $ 6.54万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580375
• 关键词: Acceleration; Adult; Affect; Albuminuria; Antisense Oligonucleotides; Apolipoproteins; Atherosclerosis; Attenuated; Blood Glucose; Cardiovascular Diseases; Cause of Death; Cells; Chylomicrons; Complement; Complement 3a; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Data; Dependovirus; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dyslipidemias; Endothelial Cells; Epidemic; Exposure to; Funding; Future; Hepatic; High Density Lipoproteins; Human; Hypertriglyceridemia; Impaired Renal Function; Impairment; In Vitro; Infiltration; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; LDL Cholesterol Lipoproteins; Life; Link; Lipids; Lipoproteins; Liver; Mediating; Metabolism; Modeling; Mus; Myeloid Cells; Nephrectomy; Non-Insulin-Dependent Diabetes Mellitus; Patients; Persons; Pharmacologic Substance; Phenotype; Plasma; Play; Population; Process; Renal function; Residual state; Risk; Risk Factors; Role; Serum; Severity of illness; Techniques; Testing; Triglycerides; Very low density lipoprotein; cardiovascular disorder risk; chemokine receptor; diabetic; inhibitor; macrophage; monocyte; mouse model; new therapeutic target; non-diabetic; novel; novel therapeutics; overexpression; parent grant; parent project; podocyte; prevent; recruit; targeted treatment; therapeutic target; transcription factor

A. SUMMARY OR ABSTRACT OF THE FUNDED PARENT GRANT OR PROJECT People with diabetes are more likely to have cardiovascular disease (CVD) and kidney disease. Most of the excess risk of CVD in diabetes is restricted to patients with diabetes and diabetic kidney disease (DKD). New data indicates that apolipoprotein C3 (APOC3) plays a critical role in diabetic atherosclerosis and preliminary data suggests that it is causally linked to DKD. APOC3 is a key regulator of triglyceride-rich lipoprotein (TRL) metabolism. It is in turn regulated by insulin, but also by kidney disease. Our overall hypothesis is that diabetes and kidney disease raise APOC3 levels. Increased levels of TRLs and their remnants, driven by APOC3, accelerate diabetic kidney disease as well as atherosclerosis. This hypothesis will be tested in 2 separate aims: Aim 1: Does blocking APOC3 prevent diabetic kidney disease? This will be tested in 2 different mouse models of diabetes and kidney disease using 2 different approaches to target APOC3; a specific antisense (ASO) to APOC3 and a transcription factor (CREBH) that has profound effects selectively on TRL- associated APOC3. Aim 2: Does renal impairment and diabetes act synergistically to elevate APOC3, contributing atherosclerosis? To test the hypothesis that diabetes and reduced renal function act synergistically to elevate plasma APOC3 to accelerate atherosclerosis we will induce renal impairment in non- diabetic and diabetic mice using 5/6 nephrectomy. APOC3 levels will be reduced in these mice using both APOC3 ASO treatment and hepatic overexpression of CREBH to test the causal role of APOC3. The majority of the excessive CVD risk in diabetes is present in patients who also have DKD. With the diabetic population growing, finding new therapeutic targets is exceedingly important. We propose a novel common mechanism whereby DKD and CVD are accelerated by APOC3-mediated increases in TRLs and their remnants, and a new way that both can be prevented by blocking APOC3. These studies are likely to reveal important similarities in the mechanisms whereby APOC3 promotes two of the major complications of diabetes. A human APOC3 ASO has already been tested in T2DM patients with promising TRL-lowering results, thus APOC3 might be a therapeutic target for combating the rising epidemic of diabetic complications.

A. 受资助的母公司补助金或项目的摘要或摘要 糖尿病患者更有可能患有心血管疾病 (CVD) 和肾脏疾病。大部分的 糖尿病中 CVD 风险过高仅限于患有糖尿病和糖尿病肾病 (DKD) 的患者。新的 数据表明，载脂蛋白C3（APOC3）在糖尿病动脉粥样硬化和初步研究中发挥着关键作用。 数据表明它与 DKD 存在因果关系。 APOC3 是富含甘油三酯的脂蛋白 (TRL) 的关键调节因子 代谢。它反过来又受到胰岛素的调节，也受到肾脏疾病的调节。我们的总体假设是糖尿病 肾脏疾病会提高 APOC3 水平。在 APOC3 的驱动下，TRL 及其残余物的水平增加， 加速糖尿病肾病以及动脉粥样硬化。该假设将在 2 个单独的 目标： 目标 1：阻断 APOC3 能否预防糖尿病肾病？这将在 2 个不同的环境中进行测试 使用 2 种不同方法靶向 APOC3 的糖尿病和肾病小鼠模型；一个具体的 APOC3 的反义 (ASO) 和转录因子 (CREBH)，选择性地对 TRL- 产生深远影响 相关 APOC3。目标 2：肾功能损害和糖尿病是否协同作用以升高 APOC3、 导致动脉粥样硬化？检验糖尿病和肾功能下降起作用的假设 协同提高血浆APOC3以加速动脉粥样硬化，我们将诱导非-肾损伤 使用 5/6 肾切除术的糖尿病和糖尿病小鼠。使用这两种方法将降低这些小鼠的 APOC3 水平 APOC3 ASO 处理和 CREBH 肝脏过度表达，以测试 APOC3 的因果作用。大多数 糖尿病患者的 CVD 风险过高也存在于患有 DKD 的患者中。与糖尿病人群 随着疾病的不断发展，寻找新的治疗靶点显得尤为重要。我们提出了一种新颖的通用机制 APOC3 介导的 TRL 及其残余物的增加会加速 DKD 和 CVD，并且 通过阻止 APOC3 可以预防这两种情况的新方法。这些研究可能会揭示重要的 APOC3 促进糖尿病两种主要并发症的机制有相似之处。一个人类 APOC3 ASO 已在 T2DM 患者中进行了测试，具有有望降低 TRL 的结果，因此 APOC3 可能是对抗日益流行的糖尿病并发症的治疗目标。