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

• 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
• 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

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(静脉和人工搭桥、血管成形术、支架、 动脉内膜切除术等)由于血管壁再闭塞，故障率高得令人无法接受 适应症，大多数失败以内膜增生为主。人类进化出了复杂的机制 应对压力，如血管创伤，并从中恢复。饮食摄入量和在此期间的模式 进化压力与当代西方国家持续的高蛋白摄入量截然不同 节食。饮食限制(在没有营养不良的情况下减少食物摄入量)因延长寿命而广为人知 物种。我们和其他人最近发表的研究表明，仅有短暂的饮食蛋白质限制(DPR) 这也是一种积极影响新陈代谢健康和抵抗多种形式的急性应激的方法， 包括动脉和静脉移植物对损伤的血管反应。我们广泛地理论上认为，脂肪-a 优势、高度生物活性但灵活的组织-可以通过短期DPR预先调整为积极 通过特定的信号网络影响静脉移植物的壁适应。 在这里，我们检验了这样的假设：短期的DPR通过抑制移植静脉的内膜增生 基质血管成分中的营养感受器分子mTORC1和瘦素依赖机制 局部脂肪组织。该项目将完成三个具体目标：1)描述随着时间的推移， 短期DPR对特定间隔的脂肪和移植静脉壁内膜增生和重塑的影响。2) 明确DPR的脂肪mTORC1依赖机制，因为它们与移植静脉壁内膜增生有关 3)确定瘦素信号在移植静脉壁DPR减弱中的作用 改编。 这项工作建立在申请人的多篇同行评议出版物的基础上，并建立了 与营养和血管生物学专家建立伙伴关系。完成这些目标将揭开小说的面纱 术前DPR、促炎性脂肪因子/细胞因子分泌、mTORC1之间的机制联系 /瘦素信号通路，以及它们与早期静脉移植适应的联系。这些发现应该是 可翻译为临床实践，作为机械信息，有针对性的辅助营养和医疗 延长闭塞血管疾病介入治疗的耐久性的治疗。