PPAR-gamma Deacetylation in Cardiometabolic Disease

心脏代谢疾病中的 PPAR-gamma 脱乙酰化

• 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
• 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

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 减少2型动脉粥样硬化心血管（CV）疾病的事件，严重性和并发症 糖尿病仍然是未满足的关键医疗需求。胰岛素抵抗易于动脉粥样硬化，使其恶化 2型糖尿病患者的大血管并发症。虽然新的抗血糖药物提供 希望降低糖尿病中简历事件风险的希望，相对疾病燃烧仍然很大。那， 需要解决糖尿病发病机理的其他方面的治疗，最著名的是胰岛素抵抗。 最近的一项研究表明，对胰岛素传感器对动脉粥样硬化的影响的兴趣重新点燃了 噻唑烷二酮（TZD）胰岛素敏化剂，吡格列酮，降低了脑血管事件的复发风险 抗胰岛素抗药性患者最近患有缺血性中风或短暂性缺血性发作。但是，使用这些 特工受到严重不良事件的伤害，包括担心充血性心力衰竭，骨折和 膀胱癌。在该PPG支持的研究中。 Accili和Qiang表明TZDS调节 通过将两个氨基酸残基K268和K293脱乙酰基，其靶PPARG的功能。他们证明了 PPARG的TZD依赖性脱乙酰化调节了后者激活或复制靶基因的能力。在 初步数据，它们表明，用于PPARG的敲入等位基因的纯合子导致其本构成 脱乙酰基（K268R和K293R，因此2KR）保持对金列酮的胰岛素敏感反应 治疗，但不要显示骨密度降低或液体保留和心率增加。此外，在 与Drs合作。塔巴斯（Tabas）和高个子，他们表明2kr小鼠的动脉粥样硬化斑块形成减少 与WT相比，2kR巨噬细胞中过表达PCSK9和for经核细胞增多量大大增加。 pis 假设在LDLR - / - 背景上转移时，2kr突变体PPARG（a）会下降 斑块形成，（b）减少TZD处理对骨质流失，心脏肥大和液体的不利影响 平衡，（c）促进用TZD治疗的已建立病变的动物动脉粥样硬化消退。到 检验假设，他们将：在AIM 1中研究2KR突变对动脉粥样硬化进展和 使用LDL受体基因敲除小鼠（LDLR - / - ）的杂交回归，然后是骨髓移植到 确定预期保护作用的主要位点。他们还将检查2kr-dll-/ - 鼠标是否是 免受罗格列酮的不利影响。在AIM 2中，他们将研究2KR在巨噬细胞功能中的影响， 专注于胞吐作用（TABAS协作）和胆固醇外排（高层协作）；在目标3中，他们将 寻求通过将基因表达与基因表达与 全基因组组蛋白的修饰和巨噬细胞的增强剂研究。