Adipose Dependent Mechanisms of Dietary Protein Restriction Protective Effects on Vein Graft Adaptations

膳食蛋白质限制对静脉移植物适应的保护作用的脂肪依赖性机制

基本信息

批准号：
9293362
负责人：
C KEITH OZAKI
金额：
$ 42.79万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293362
关键词：
Acute Adipocytes Adipose tissue Amino Acids Angioplasty Arterial Occlusive Diseases Arteries Attenuated Biological Biological Factors Biology Blood Vessels Brain Bypass Caloric Restriction Cardiovascular Diseases Clinical Complex Coronary Artery Bypass Cytokine Signaling Data Development Diet Dietary Practices Dietary Proteins Dietary intake Endarterectomy Endocrine Environment Equilibrium Essential Amino Acids FRAP1 gene Failure Fatty acid glycerol esters Foundations Genetic Health Health Benefit Hormones Human Hyperplasia ICAM1 gene Immune response Infarction Injury Intake Intervention Leptin Lesion Link Longevity Lower Extremity Malnutrition Mammals Mediator of activation protein Medical Metabolic Metabolic syndrome Modeling Morbidity - disease rate Mus Nutrient Nutritional Operative Surgical Procedures Organ Pathway interactions Patients Peer Review Peripheral arterial disease Pharmacology Plague Procedures Process Production Property Prosthesis Proteins Publications Publishing Regulation Reperfusion Therapy Research Resistance Rodent Role Signal Pathway Signal Transduction Signal Transduction Pathway Stents Stress Stroke TNF gene TSC1 gene Testing Time Tissues Transplantation Trauma Treatment Efficacy Vascular Diseases Vascular remodeling Vein graft Veins Work acute stress adipokines aging population attenuation clinical practice cytokine dietary restriction fitness graft failure healing improved liver ischemia loss of function macrophage mortality novel novel strategies nutrition paracrine pressure protective effect protein intake reduced food intake response response to injury sensor small molecule stressor subcutaneous therapeutic target western diet

项目摘要

Therapies for occlusive arterial disease (vein and prosthetic bypasses, angioplasties, stents, endarterectomies, etc.) suffer from unacceptably high failure rates due to re-occlusive vascular wall adaptations, with intimal hyperplasia dominating most failures. Humans have evolved complex mechanisms to respond to and heal from stress such as vascular trauma. Dietary intake and patterns during these evolutionary pressures were quite different than the constant high protein intake of contemporary Western diets. Dietary restriction (reduced food intake without malnutrition) is known for extending longevity in multiple species. Recent published work by us and others has shown that brief dietary protein restriction (DPR) alone is also an approach to positively impact metabolic fitness and resistance to multiple forms of acute stress, including the vascular response to injury in arteries as well as vein grafts. We broadly theorize that adipose—a dominant, highly biologically active yet nimble tissue—can be pre-conditioned by short-term DPR to positively impact vein graft wall adaptations via specific signaling networks. Herein we test the hypothesis that short-term DPR attenuates vein graft intimal hyperplasia via the nutrient sensor molecule mTORC1 and leptin dependent mechanisms in the stromal vascular fraction of local adipose tissue. The project will complete three Specific Aims: 1) Delineate over time the impact of short-term DPR on specific compartments of adipose and vein graft wall intimal hyperplasia and remodeling. 2) Define adipose mTORC1 dependent mechanisms of DPR as they relate to vein graft wall intimal hyperplasia and wall remodeling 3) Determine the role of leptin signaling in DPR attenuation of the vein graft wall adaptations. This work builds on a foundation of multiple peer reviewed publications by the applicant, and established partnerships with experts in nutrition and vascular biology. Completion of these aims will uncover novel mechanistic links between pre-operative DPR, proinflammatory adipokine/cytokine secretion, the mTORC1 /leptin signaling pathways, and their links with early vein graft adaptations. These findings should be translatable to clinical practice as mechanistically informed, targeted adjunctive nutritional and medical therapies to prolong the durability of occlusive vascular disease interventions.

闭塞性动脉疾病的治疗（静脉和假体旁路、血管成形术、支架、动脉内膜切除术等）由于血管壁重新闭塞而导致失败率高得令人无法接受适应，其中内膜增生主导了大多数失败。应对血管创伤等压力并从中恢复。在此期间的饮食摄入和模式。进化压力与当代西方人持续高蛋白质摄入量有很大不同饮食限制（减少食物摄入而不造成营养不良）可以延长多种疾病的寿命。我们和其他人最近发表的研究表明，仅短期饮食蛋白质限制（DPR）即可。也是一种积极影响代谢健康和抵抗多种形式急性压力的方法，包括血管对动脉和静脉移植物损伤的反应，我们广泛地推测脂肪是一种占主导地位的、高度生物活性但灵活的组织——可以通过短期 DPR 进行预处理，以积极地发挥作用通过特定的信号网络影响静脉移植壁的适应。在此，我们检验了短期 DPR 通过以下方式减弱静脉移植物内膜增生的假设：基质血管部分中的营养传感器分子 mTORC1 和瘦素依赖性机制该项目将完成三个具体目标：1) 描绘随着时间的推移所产生的影响。短期 DPR 对脂肪和静脉移植壁内膜增生和重塑的特定隔室2)。定义 DPR 的脂肪 mTORC1 依赖性机制，因为它们与静脉移植壁内膜增生有关和壁重塑 3) 确定瘦素信号传导在静脉移植壁 DPR 衰减中的作用适应。这项工作建立在申请人发表的多个同行评审出版物的基础上，并建立了与营养和血管生物学专家的合作将发现新的目标。术前 DPR、促炎脂肪因子/细胞因子分泌、mTORC1 之间的机制联系 /瘦素信号通路及其与早期静脉移植适应的联系。可转化为临床实践，作为机械性的、有针对性的辅助营养和医疗延长闭塞性血管疾病干预措施的持久性的疗法。