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

• 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
• 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

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.

项目总结/摘要 肥胖症的患病率在全球范围内不断增加，慢性全身性和脂肪组织（AT）炎症在全球范围内不断增加。 肥胖会增加患心血管疾病（CVD）的风险。虽然几种抗炎剂 已经显示出减少不良心血管（CV）结局的益处，但没有一种是肥胖症的标准治疗。 因此，仍然存在CV事件的剩余风险，并且显著需要新的治疗剂来靶向 肥胖症的炎症和预防或逆转这些结果。此外，我们对AT 由于在临床试验中难以获得样品，以及在动物中的发现， 翻译不一致。SLGT 2抑制剂通过未知途径减少主要不良CV事件 机制和超出预期的抗高血糖或减肥的好处。一个反- SGLT 2抑制的炎症效应已在动物中得到证实，如果存在于人体中， 指出了CV益处的潜在机制。我们的中心假设是SGLT 2抑制剂降低了 并导致内皮功能改善作为CVD的替代物。与 一个结合了临床研究设计、AT免疫学和内皮测量专业知识的指导团队，我们 可以解决这一科学空白，并促进我们对SGLT 2抑制的CV益处的理解。我们 研究小组将招募患有糖尿病前期的肥胖个体，并使用12周的SGLT 2抑制剂或 安慰剂在一项随机双盲试验中。在目标1中，我们将检测SGLT 2抑制是否降低AT， 通过定量免疫细胞群体和转录物来检测全身性炎症。在目标2中，我们将测试 SGLT 2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SGLT 2抑制对免疫和内皮细胞的分子效应， 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 从开始到完成进行机械人体试验;（目标2）建立和领导一个 在免疫学，AT生物学和CVD交叉的多学科计划;（目标3）开发 在体外分析免疫和内皮细胞相互作用的专业知识;和（目标4）获得研究 心血管疾病替代指标的技能。这些目标将帮助候选人实现她的长期目标。 职业目标是在免疫功能和血管疾病的界面上领导一个转化研究项目 并为预防和治疗心脏代谢疾病的靶向干预确定新的途径。 她将在一个拥有支持早期职业生涯的巨大记录的机构内实现这些目标 物理科学家她还得到了一个出色的辅导团队的支持， 许多医生，科学家的自主权，并有一个多样化和多学科的利益， 与候选人不同，但反映和增强候选人的能力。