PPAR-gamma Deacetylation in Cardiometabolic Disease

心脏代谢疾病中的 PPAR-gamma 脱乙酰化

基本信息

批准号：
10428379
负责人：
DOMENICO ACCILI
金额：
$ 54.68万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10428379
关键词：
Acetylation Address Adipose tissue Adverse effects Agonist Alleles Amino Acid Substitution Amino Acids Animals Antiatherogenic Arterial Fatty Streak Atherosclerosis Biguanides Blood Vessels Bone Density Bone Marrow Bone Marrow Transplantation Candidate Disease Gene Cardiometabolic Disease Cardiovascular system Cholesterol Chromatin Clinic Clinical Collaborations Congestive Heart Failure Data Deacetylation Diabetes Mellitus Drug Industry Energy Metabolism Enhancers Event Failure Fluid Balance Fracture Gene Expression Gene Expression Regulation Generations Genes Heart Hypertrophy Heart Rate Hematopoietic High Fat Diet Histones Homeostasis Hypoglycemic Agents Incidence Inflammation Insulin Resistance Ischemic Stroke Knock-in Knockout Mice Lesion Light Lipids Liquid substance Low Density Lipoprotein Receptor Lysine Malignant neoplasm of urinary bladder Mediating Mediator of activation protein Medical Metabolic Metformin Methylation Modeling Molecular Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Oncogenic PPAR gamma Pathogenesis Patients Phagocytes Pharmaceutical Preparations Pioglitazone Play Posture Predisposition Process Property Recurrence Regulation Risk Role SIRT1 gene Serious Adverse Event Severities Sir2-like Deacetylases Site Testing Therapeutic Thermogenesis Thiazolidinediones Tissues Transient Ischemic Attack Ursidae Family Weight Gain atherogenesis atheroprotective bone bone loss burden of illness cardiovascular risk factor cerebrovascular clinically relevant comorbidity diabetes pathogenesis genome-wide high risk population histone modification improved insulin sensitivity insulin sensitizing drugs interest macrophage macrovascular disease mutant non-diabetic overexpression prevent protective effect response retention rate rosiglitazone side effect transcription factor transcriptome sequencing

项目摘要

ABSTRACT Reducing the incidence, severity, and complications of atherosclerotic cardiovascular (CV) disease in type 2 diabetes remains a key unmet medical need. Insulin resistance predisposes to atherosclerosis and worsens its macrovascular complications in patients with type 2 diabetes. While new anti-hyperglycemic drugs offer glimmers of hope to reduce the risk of CV events in diabetes, the relative disease burden remains large. Thus, treatments that address other aspects of diabetes pathogenesis, most notably insulin resistance, are needed. Interest in the effects of insulin sensitizers on atherosclerosis was rekindled by a recent study showing that the thiazolidinedione (TZD) insulin-sensitizer, pioglitazone, reduced the recurrence risk of cerebrovascular events in insulin-resistant patients with a recent ischemic stroke or transient ischemic attack. However, use of these agents is marred by serious adverse events, including worsening of congestive heart failure, fractures, and bladder cancer. In studies supported by this PPG, Drs. Accili and Qiang have shown that TZDs regulate the function of their target PPARg by deacetylating two amino acid residues, K268 and K293. They demonstrated that TZD-dependent deacetylation of PPARg modulates the latter’s ability to activate or repress target genes. In preliminary data, they show that mice homozygous for knock-in alleles of PPARg resulting in its constitutive deacetylation (K268R and K293R, thus 2KR) maintain the insulin-sensitizing response to rosiglitazone treatment, but don’t show reduced bone density, or increased fluid retention and heart rate. Further, in collaboration with Drs. Tabas and Tall, they show that atherosclerosis plaque formation is reduced in 2KR mice overexpressing PCSK9, and efferocytosis greatly increased in 2KR macrophages compared to WT. The PIs hypothesize that, when transferred on the Ldlr–/– background, the 2KR mutant PPARg will (a) decrease plaque formation, (b) reduce the adverse effects of TZD treatment on bone loss, cardiac hypertrophy, and fluid balance, and (c) promote atherosclerosis regression in animals with established lesions treated with TZD. To test the hypothesis, they will: in Aim 1 study the effect of the 2KR mutation on atherosclerosis progression and regression using crosses with Ldl receptor knockout mice (Ldlr–/–), followed by bone marrow transplants to determine the main site(s) of the expected protective effect. They will also examine whether 2KR-Ldlr–/– mice are protected from rosiglitazone’s adverse effects. In Aim 2 they will study the effect of 2KR in macrophage function, with a focus on efferocytosis (Tabas collaboration) and cholesterol efflux (Tall collaboration); in Aim 3 they will seek to identify the critical mediators of 2KR action by an integrative approach combining gene expression with genome-wide histone modification and enhancer studies in macrophages.

抽象的降低 2 型动脉粥样硬化性心血管 (CV) 疾病的发生率、严重程度和并发症糖尿病仍然是一个未得到满足的关键医疗需求。胰岛素抵抗会导致动脉粥样硬化并使其恶化。新型抗高血糖药物可缓解 2 型糖尿病患者的大血管并发症。降低糖尿病心血管事件风险的一线希望，但相对疾病负担仍然很大。需要解决糖尿病发病机制其他方面的治疗，尤其是胰岛素抵抗。最近的一项研究重新激起了人们对胰岛素增敏剂对动脉粥样硬化的影响的兴趣，该研究表明，噻唑烷二酮（TZD）胰岛素增敏剂吡格列酮可降低脑血管事件的复发风险近期发生过缺血性中风或短暂性脑缺血发作的胰岛素抵抗患者可使用这些药物。药物会受到严重不良事件的影响，包括充血性心力衰竭、骨折和在该 PPG 支持的研究中，Accili 和 Qiang 博士表明 TZD 可以调节膀胱癌。他们证明了通过脱乙酰两个氨基酸残基 K268 和 K293 来发挥其靶标 PPARg 的功能。 TZD 依赖性 PPARg 去乙酰化调节后者激活或抑制靶基因的能力。初步数据显示，PPARg 敲入等位基因纯合的小鼠导致其组成型脱乙酰化（K268R 和 K293R，即 2KR）维持对罗格列酮的胰岛素增敏反应治疗，但没有显示骨密度降低，或液体潴留和心率增加。与 Tabas 和 Tall 博士合作，他们发现 2KR 小鼠的动脉粥样硬化斑块形成减少与 WT 相比，2KR 巨噬细胞过度表达 PCSK9，胞吞作用大大增加。保留，当转移到 Ldlr–/– 背景上时，2KR 突变体 PPARg 将 (a) 减少斑块形成，(b) 减少 TZD 治疗对骨质流失、心脏肥大和体液的不利影响 (c) 促进已用 TZD 治疗病变的动物的动脉粥样硬化消退。为了检验这一假设，他们将：在目标 1 中研究 2KR 突变对动脉粥样硬化进展的影响，以及使用与 Ldl 受体敲除小鼠 (Ldlr–/–) 杂交进行回归，然后进行骨髓移植他们还将检查 2KR-Ldlr–/– 小鼠是否是预期保护作用的主要位点。免受罗格列酮的不利影响在目标 2 中，他们将研究 2KR 对巨噬细胞功能的影响，他们将在目标 3 中重点关注胞吞作用（Tabas 合作）和胆固醇流出（Tall 合作）；寻求通过基因表达与巨噬细胞的全基因组组蛋白修饰和增强子研究。