The Effect of SGLT2 Inhibition on Adipose Tissue Inflammation and Endothelial Function

SGLT2 抑制对脂肪组织炎症和内皮功能的影响

基本信息

批准号：
10591914
负责人：
Mona Mashayekhi
金额：
$ 18.54万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591914
关键词：
Address Adipose tissue Animals Anti-Inflammatory Agents Antigen-Antibody Complex Antiinflammatory Effect Aorta Biology Blood Blood Vessels Body Weight decreased Cardiometabolic Disease Cardiovascular Diseases Cardiovascular system Cell Adhesion Molecules Cell Communication Cells Chronic Clinical Research Clinical Trials Coculture Techniques Confocal Microscopy Data Development Diabetes Mellitus Double-blind trial Endothelial Cells Endothelium Enrollment Environment Event Flow Cytometry Future Glucose Goals Heart Diseases Human Hypoglycemic Agents Immune Immunology In Vitro Inflammasome Inflammation Inflammatory Institution Intercellular adhesion molecule 1 Interleukin-6 Intervention Knowledge Lead Link Macrophage Measures Mediating Mentors Microscopy Molecular Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated cardiovascular disease Operative Surgical Procedures Outcome Pathway interactions Patients Pharmaceutical Preparations Physicians Placebos Population Prediabetes syndrome Prevalence Production Randomized Randomized, Controlled Trials Regulatory T-Lymphocyte Research Research Design Residual state Risk Sampling Scientist Sodium Suction Lipectomy T-Lymphocyte Testing Therapeutic Intervention Transcript Translating Vascular Diseases Venous Visceral bariatric surgery cardiovascular disorder risk cardiovascular risk factor career circulating biomarkers cohort design endothelial dysfunction experience heart disease risk immune function improved inflammatory marker inhibitor interest multidisciplinary novel therapeutics obese patients obese person prevent programs randomized trial response sequencing platform skills standard of care subcutaneous symporter systemic inflammatory response targeted treatment transcriptome sequencing translational research program translational scientist

项目摘要

Project Summary/Abstract The prevalence of obesity is increasing globally, and chronic systemic and adipose tissue (AT) inflammation in obesity contribute to increased risk of cardiovascular disease (CVD). While several anti-inflammatory agents have shown benefit in reducing adverse cardiovascular (CV) outcomes, none are standard of care in obesity. Thus, there remains a residual risk of CV events and a significant need for new therapeutics to target the inflammation in obesity and prevent or reverse these outcomes. Furthermore, our understanding of AT inflammation in humans is limited due to difficulty obtaining samples in clinical trials, and discoveries in animals do not consistently translate. SLGT2 inhibitors reduce major adverse CV events through unknown mechanism(s) and beyond what is expected from their anti-hyperglycemic or weight loss benefits. An anti- inflammatory effect of SGLT2 inhibition has been demonstrated in animals, and if present in humans could point to a potential mechanism for the CV benefit. Our central hypothesis is that SGLT2 inhibitors decrease systemic and AT inflammation and result in improvements in endothelial function as a surrogate of CVD. With a mentoring team combining expertise in clinical study design, AT immunology and endothelial measures, we can address this scientific gap and advance our understanding of the CV benefits of SGLT2 inhibition. Our team will enroll obese individuals with pre-diabetes and treat them with 12 weeks of an SGLT2 inhibitor or placebo in a randomized double-blind trial. In Aim 1, we will test that SGLT2 inhibition reduces AT and systemic inflammation by quantifying immune cell populations and transcripts. In Aim 2, we will test that SGLT2 inhibition reduces endothelial inflammation and improves endothelial vasodilatory function. We will assess whether changes in endothelial function are associated with changes in AT and systemic inflammation. In Aim 3, we will interrogate the molecular effects of SGLT2 inhibition on immune and endothelial cell interactions in vitro. Through the activities in this proposal, the candidate will (Objective 1) design and implement a mechanistic human trial from inception to completion; (Objective 2) establish and lead a multidisciplinary program at the intersection of immunology, AT biology and CVD; (Objective 3) develop expertise in analyzing immune and endothelial cell interactions in vitro; and (Objective 4) gain investigative skills in surrogate measures of CVD. These objectives will assist the candidate in achieving her long-term career goal to lead a translational research program at the interface of immune function and vascular disease in obesity and define new pathways for targeted interventions to prevent and treat cardiometabolic diseases. She will accomplish these goals within an institution with a tremendous track record of supporting early career physician-scientists. She also has the support of an exceptional mentoring team that has jointly mentored many physician-scientists to autonomy, and that has a diverse and multidisciplinary set of interests that are distinct from, yet mirror and enhance those of the candidate.

项目概要/摘要全球肥胖患病率不断增加，慢性全身炎症和脂肪组织 (AT) 炎症在全球范围内不断增加肥胖会增加心血管疾病（CVD）的风险。虽然有几种抗炎药已显示出在减少不良心血管 (CV) 结局方面的益处，但都不是肥胖症的标准治疗方法。因此，仍然存在心血管事件的残余风险，并且非常需要新的治疗方法来针对肥胖中的炎症并预防或逆转这些结果。此外，我们对AT的理解由于在临床试验中难以获取样本以及在动物身上的发现，人类炎症的发生受到限制翻译不一致。 SLGT2 抑制剂通过未知方式减少主要不良心血管事件机制并超出其抗高血糖或减肥功效的预期。一个反 SGLT2 抑制的炎症效应已在动物身上得到证实，如果存在于人类中，指出了 CV 益处的潜在机制。我们的中心假设是 SGLT2 抑制剂减少全身炎症和 AT 炎症，并导致内皮功能的改善，作为 CVD 的替代。和我们的指导团队结合了临床研究设计、AT 免疫学和内皮测量方面的专业知识可以弥补这一科学差距，并加深我们对 SGLT2 抑制对 CV 益处的理解。我们的研究小组将招募患有糖尿病前期的肥胖个体，并用 SGLT2 抑制剂治疗他们 12 周，或者随机双盲试验中的安慰剂。在目标 1 中，我们将测试 SGLT2 抑制是否会降低 AT 和通过量化免疫细胞群和转录本来识别全身炎症。在目标 2 中，我们将测试 SGLT2 抑制可减少内皮炎症并改善内皮血管舒张功能。我们将评估内皮功能的变化是否与 AT 和全身炎症的变化相关。在目标 3 中，我们将探讨 SGLT2 抑制对免疫细胞和内皮细胞的分子影响体外相互作用。通过本提案中的活动，候选人将（目标 1）设计和从开始到结束实施机械人体试验；（目标 2）建立并领导一个免疫学、AT 生物学和 CVD 交叉领域的多学科项目；（目标3）发展体外分析免疫和内皮细胞相互作用的专业知识； (目标 4) 进行调查 CVD 替代测量的技能。这些目标将帮助候选人实现她的长期目标职业目标是领导免疫功能和血管疾病界面的转化研究项目肥胖症的研究，并确定预防和治疗心脏代谢疾病的有针对性的干预措施的新途径。她将在一个拥有支持早期职业生涯的良好记录的机构内实现这些目标医生科学家。她还得到了一个杰出的指导团队的支持，该团队共同指导了许多医师科学家都具有自主权，并且具有多样化和多学科的兴趣与候选人不同，但反映并增强了候选人的能力。