Aging and Hepatic Microvascular Dysfunction

衰老与肝微血管功能障碍

基本信息

批准号：
7244112
负责人：
ROBERT S MCCUSKEY
金额：
$ 11.17万
依托单位：
UNIVERSITY OF ARIZONA
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 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7244112
关键词：
Adherence Advanced Glycosylation End Products Affect Age Age-Months Aging Animals Applications Grants Area Atherosclerosis Basal lamina Biochemical Blood Blood flow Caliber Cell Adhesion Molecules Cell physiology Cells Cellular Morphology Clinical Condition Connective Tissue Constriction procedure Critiques Cytoskeletal Modeling Deposition Development Discontinuous Capillary Dose Electrons Endocytic Vesicle Endocytosis Endothelial Cells Endothelin Endothelin-1 Endothelium Event Experimental Designs Extracellular Matrix Free Radical Formation Functional disorder Growth Factor Hepatic Hepatocyte Hormones Hyaluronan Immunohistochemistry In Vitro Incubated Indium Individual Inflammatory Inflammatory Response Ischemia Kupffer Cells Labyrinth fenestration Lasers Leukocytes Ligands Light Link Lipids Literature Liver Liver parenchyma Low-Density Lipoproteins Maintenance Measurement Measures Mediator of activation protein Membrane Metabolism Methods Microcirculation Microscopic Microscopy Molecular Mus Nature Neonatal Nitric Oxide Nitrogen Numbers Oxidative Stress Oxygen Pattern Peripheral Perisinusoidal Space Pharmaceutical Preparations Phenotype Plasma Platelet aggregation Play Predisposition Procedures Process Production Rate Rattus Reaction Relative (related person)Reporting Research Personnel Resolution Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Site Specimen Structure Superoxides Text Therapeutic Thinking Time Tissues Toxin Variant Western Blotting Xenobiotics age effect age related chylomicron remnant cytokine day drug metabolism glycation human NOS3 protein in vivo meter novel numb protein programs receptor receptor expression receptor for advanced glycation endproducts receptor function research study response scavenger receptor stellate cell success uptake vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Aging of the liver is associated with reductions in its mass as well as a 30-50% reduction in blood flow accompanied by an impaired metabolism and potential clinical implications including adverse drug reactions, susceptibility to toxins, and atherosclerosis. The reason for this age related reduction in hepatic blood flow is not known. However, significant age associated reductions in the fenestration of hepatic sinusoidal endothelial cells (SEC) and increased deposition of extracellular matrix, basal lamina, and connective tissue in the Space of Disse leading to "pseudocapillarization" of the SEC are thought to affect the transfer of substrates including oxygen, chylomicron remnants, toxins, and drugs between the blood and hepatic parenchymal cells. What functional alterations in SEC accompany "pseudocapillarization" are not clear but may play a significant role in the age related diminished blood flow. Accumulation of advanced glycation end-products (AGEs) also occurs with aging in SEC, but its effects on SEC and microvascular function are unknown. We hypothesize that age associated reductions in hepatic blood flow and SEC morphology are due the accumulation of AGE in these cells causing reduced production of constitutive nitric oxide (NO) and/or enhanced production of endothelin-1 (ET-1) and sinusoid constriction perhaps accompanied by an hepatic microvascular inflammatory response. To validate this hypothesis, the livers of mice will be studied at 0.8, 3.3,14, and 27 months of age. In vivo microscopy will be used to determine the dynamic spatial and temporal development of hepatic microvascular dysfunction. Light and electron microscopic examination of fixed specimens and isolated SEC will evaluate structural alterations that can not be visualized in vivo. These will be correlated with measurements of the accumulation of AGE in SEC and changes in NO, eNOS, ET-1, proinflammatory cytokines, and superoxide in SEC and liver to gain clues to explain the responses observed microscopically. The results should provide novel, new information about the aging liver.

描述（由申请人提供）：肝脏老化与其质量减少以及血流量减少 30-50% 相关，并伴有新陈代谢受损和潜在的临床影响，包括药物不良反应、对毒素的敏感性和动脉粥样硬化。与年龄相关的肝血流量减少的原因尚不清楚。然而，与年龄相关的肝窦内皮细胞（SEC）开窗显着减少，以及细胞外基质、基底层和迪斯间隙结缔组织沉积增加，导致 SEC 的“假毛细血管化”，被认为影响了肝窦内皮细胞的转移。血液和肝实质细胞之间的底物包括氧气、乳糜微粒残留物、毒素和药物。 SEC 的哪些功能改变伴随“假毛细血管化”尚不清楚，但可能在与年龄相关的血流减少中发挥重要作用。随着 SEC 的衰老，晚期糖基化终末产物 (AGE) 也会发生积累，但其对 SEC 和微血管功能的影响尚不清楚。我们假设年龄相关的肝血流量和 SEC 形态减少是由于这些细胞中 AGE 的积累导致组成型一氧化氮 (NO) 产生减少和/或内皮素-1 (ET-1) 产生增加和血窦收缩并伴有肝脏微血管炎症反应。为了验证这一假设，将对 0.8、3.3、14 和 27 个月龄小鼠的肝脏进行研究。体内显微镜将用于确定肝微血管功能障碍的动态空间和时间发展。对固定样本和分离的 SEC 进行光学和电子显微镜检查将评估体内无法观察到的结构变化。这些将与 SEC 中 AGE 积累的测量以及 SEC 和肝脏中 NO、eNOS、ET-1、促炎细胞因子和超氧化物的变化相关，以获得解释显微镜下观察到的反应的线索。研究结果应该提供有关衰老肝脏的新颖的信息。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hepatic disposal of advanced glycation end products during maturation and aging.

成熟和衰老过程中晚期糖基化终产物的肝脏处理。

DOI：
10.1016/j.exger.2013.03.005
发表时间：
2013-06
期刊：
Experimental gerontology
影响因子：
3.9
作者：
Svistounov D;Oteiza A;Zykova SN;Sørensen KK;McCourt P;McLachlan AJ;McCuskey RS;Smedsrød B
通讯作者：
Smedsrød B

Effects of old age on vascular complexity and dispersion of the hepatic sinusoidal network.

老年对血管复杂性和肝窦网络分散的影响。

DOI：
10.1080/10739680701600856
发表时间：
2008
期刊：
Microcirculation (New York, N.Y. : 1994)
影响因子：
0
作者：
Warren,Alessandra;Chaberek,Slawomir;Ostrowski,Kazimierz;Cogger,VictoriaC;Hilmer,SarahN;McCuskey,RobertS;Fraser,Robin;LeCouteur,DavidG
通讯作者：
LeCouteur,DavidG

大鼠肝窦内皮细胞清道夫受体介导的内吞作用的年龄相关变化。

DOI：
10.1093/gerona/glq108
发表时间：
2010
期刊：
The journals of gerontology. Series A, Biological sciences and medical sciences
影响因子：
0
作者：
Simon-Santamaria,Jaione;Malovic,Ivana;Warren,Alessandra;Oteiza,Ana;LeCouteur,David;Smedsrød,Bård;McCourt,Peter;Sørensen,KarenKristine
通讯作者：
Sørensen,KarenKristine