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：
9159129
负责人：
C KEITH OZAKI
金额：
$ 43.36万
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/9159129
关键词：
Acute Adipocytes Adipose tissue Amino Acids Angioplasty Arterial Occlusive Diseases Arteries Attenuated 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 Healed Health Health Benefit Hormones Human Humanities 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 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 Testing Therapeutic Time Tissues Transplantation Trauma 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.

闭塞动脉疾病的疗法（静脉和假体旁路，血管成形术，支架，，内侧切除术等）由于重新占用的血管壁而遭受高度高的失败率适应，内膜增生主导着大多数失败。人类将复杂的机制发展到反应并从诸如血管创伤之类的压力中治愈。在这些过程中的饮食摄入量和模式进化压力与当代西方的恒定高蛋白摄入量完全不同饮食。饮食限制（减少食物摄入而无需营养不良）以延长多种寿命而闻名物种。我们和其他人最近发表的工作表明，短暂的饮食蛋白限制（DPR）也是一种积极影响代谢适应性和对多种形式急性应力的抗性的方法，包括对动脉损伤以及静脉移植物的血管反应。我们广泛地理论上了脂肪 - 优势，高度生物学活跃但敏捷的组织 - 可以通过短期DPR预先调查通过特定的信号网络影响静脉移植壁的适应。我们在此测试了以下假设：短期DPR通过营养传感器分子MTORC1和瘦素依赖性机制局部脂肪组织。该项目将完成三个具体目标：1）随着时间的推移描述脂肪和静脉移植壁的特定隔室的短期DPR和重塑。 2）定义DPR的脂肪MTORC1依赖机制，因为它们与静脉移植壁膜膜增生有关 3）确定瘦素信号传导在静脉移植壁的DPR衰减中的作用改编。这项工作建立在申请人的多个同行审查出版物的基础上，并建立了与营养和血管生物学专家的合作伙伴关系。这些目标的完成将发现小说术前DPR，促炎脂肪因子/细胞因子分泌之间的机械联系，MTORC1 /瘦素信号通路及其与早期静脉移植适应的联系。这些发现应该是可以将机械知情，有针对性的辅助营养和医学转换为临床实践疗法延长闭塞性血管疾病干预的耐用性。