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Transplantation of Reduced-Size Fatty Livers

缩小脂肪肝移植

基本信息

批准号：
7626375
负责人：
ZHI ZHONG
金额：
$ 25.63万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7626375
关键词：
3-nitrotyrosine 4 hydroxynonenal Accounting Acetylcysteine Adenoviruses Affect Antibodies Antioxidants Apoptosis Bilirubin Bromodeoxyuridine Calories Cell Cycle Cell Proliferation Cellular biology Clinic Complex Corn Oil Cryopreservation Cyclin D1 Cyclosporine Cysteine Cytosol Data Development Diet EGF gene Electron Spin Resonance Spectroscopy Energy Supply Enzymes Failure Fatty Liver Fatty acid glycerol esters Fluorescent Probes Free Radicals Freezing Fright Functional disorder Gene Delivery Genes Goals Graft Survival Growth Factor Harvest Hepatic Hepatic Mass Histology Hydrogen Peroxide Hypoxia Image Immunohistochemistry Immunosuppressive Agents Implant Incidence Infiltration Injury Interleukin-6 Lactated Ringer&apos s Solution Liver Liver Regeneration Living Donor Liver Transplantation Manganese Superoxide Dismutase Measurement Mediating Membrane Potentials Microcirculation Microscopy Mitochondria Mitochondrial Swelling Mitotic Modeling Molecular Biology Techniques NG-Nitroarginine Methyl Ester Natural regeneration Necrosis Nitrates Nitric Oxide Nitric Oxide Synthase Nitrites Nitrogen Obese Mice Outcome Oxidation-Reduction Oxygen Pan Genus Pathway interactions Permeability Peroxonitrite Pimonidazole Play Ploidies Production Proliferating Cell Nuclear Antigen Rattus Reactive Oxygen Species Reagent Respiratory Chain Role STAT3 gene Serum Severities Signal Transduction Pathway Solutions Source Spin Trapping Staining method Stains Stress Superoxide Dismutase Superoxides Techniques Testing Time Transplantation Triglycerides UCP2 protein University of Wisconsin-lactobionate solution Western Blotting Work adduct analog base choline deficient diet clinical application cytochrome c cytokine effective therapy feeding fluorexon fluorophore graft failure graft function human NOS2A protein immunocytochemistry implantation improved in vivo inhibitor/antagonist insight intravital video microscopy liver function liver transplantation mitochondrial dysfunction mitochondrial membrane non-alcoholic oil red O polyphenol prevent research study tetramethylrhodamine methyl ester transcription factor

项目摘要

DESCRIPTION (provided by applicant): Fatty livers are rarely used for partial liver transplantation due to the fear of primary non-function. These studies are to elucidate mechanisms and to develop strategies to prevent failure of fatty partial grafts. We will use reduced-size rat liver transplantation to test the unique hypotheses that steatosis and partial liver transplantation synergistically increase reactive oxygen and nitrogen species (ROS and RNS), inhibit mitochondrial function and suppress liver regeneration. In Aim 1, we will investigate if steatosis increases graft failure after partial liver transplantation. Fatty livers will be induced by high fat diet and choline-deficient diet, respectively, and reduced to 30% to 50% of original size. We will assess survival, liver function, and histology after transplantation as a function of steatosis, graft volume and cold storage time. In Aim 2, we will test the hypothesis that ROS and RNS are increased in high-fat diet-induced fatty partial grafts, leading to injury. ROS will be determined by the spin-trapping technique and immunohistochemistry for 4-hydroxynonenal and RNS will be assessed as nitrotyrosine and nitrite/nitrate levels. We expect that ROS and RNS production will be higher in fatty than lean partial grafts. We will also identify cellular sources of ROS and RNS using fluorescent intravital multiphoton microscopy. The effects of antioxidants (Ad-superoxide dismutase, N-acetylcysteine and polyphenols) and antinitrative therapies (nitric oxide synthase inhibitors) on survival and injury of fatty partial grafts will be evaluated. In Aim 3, effects of steatosis and graft volume on energy supply will be evaluated. Uncoupling protein 2, mitochondrial permeability transition and respiratory chain activity will be determined to elucidate the mechanisms of defective energy production, and effects of mitochondrial permeability transition inhibitors and antioxidant and antinitrative therapies on mitochondrial function will be evaluated. In Aim 4, the effects of steatosis and graft volume on liver regeneration will be assessed. Cell proliferation and factors regulating regeneration (cytokines, transcription factors, growth factors, and cell cycle related genes) will be evaluated. In addition, we will investigate if protection of mitochondria function and antioxidative and antinitrative therapies improve liver regeneration. Taken together, we expect that this work will provide fundamental new insights into the mechanisms underlying reduced-size fatty graft failure and develop mechanism-based strategies to increase the use and improve the outcome of fatty livers for partial liver transplantation in the clinic.

描述（由申请人提供）：由于担心原发性无功能，脂肪肝很少用于部分肝移植。这些研究旨在阐明脂肪部分移植失败的机制，并制定预防脂肪部分移植失败的策略。我们将使用缩小体积的大鼠肝移植来测试脂肪变性和部分肝移植协同增加活性氧和氮（ROS和RNS），抑制线粒体功能和抑制肝再生的独特假设。在目标1中，我们将研究部分肝移植后脂肪变性是否会增加移植物衰竭。分别用高脂饮食和胆碱缺乏饮食诱发脂肪肝，并使脂肪肝缩小到原来的30%~ 50%。我们将评估移植后的存活率、肝功能和组织学，作为脂肪变性、移植物体积和冷藏时间的函数。在目标2中，我们将检验高脂饮食诱导的脂肪部分移植物中ROS和RNS增加导致损伤的假设。将通过自旋捕获技术测定ROS，并对4-羟基壬烯醛和RNS进行免疫组织化学评估，作为硝基酪氨酸和亚硝酸盐/硝酸盐水平。我们预计脂肪肝移植的ROS和RNS的产生要高于瘦肉肝移植。我们还将使用荧光活体多光子显微镜鉴定ROS和RNS的细胞来源。将评价抗氧化剂（Ad-超氧化物歧化酶、N-乙酰半胱氨酸和多酚）和抗硝化疗法（一氧化氮合酶抑制剂）对脂肪部分移植物存活和损伤的影响。在目标3中，将评价脂肪变性和移植物体积对能量供应的影响。将测定解偶联蛋白2、线粒体渗透性转换和呼吸链活性，以阐明能量产生缺陷的机制，并评价线粒体渗透性转换抑制剂以及抗氧化剂和抗硝酸盐治疗对线粒体功能的影响。在目标4中，将评估脂肪变性和移植物体积对肝再生的影响。将评价细胞增殖和调节再生的因子（细胞因子、转录因子、生长因子和细胞周期相关基因）。此外，我们还将研究线粒体功能的保护以及抗氧化和抗硝化治疗是否能改善肝再生。综上所述，我们期望这项工作将为缩小脂肪肝移植失败的机制提供基本的新见解，并制定基于机制的策略，以增加脂肪肝在临床部分肝移植中的使用并改善其结果。