BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10618278
• 负责人: Salman Azhar
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618278
• 关键词: Address; Adipose tissue; Adrenal Glands; Affect; Age; Aging; Alcohol abuse; Alcoholic Hepatitis; Aldosterone; Alzheimer' s Disease; American; Amyotrophic Lateral Sclerosis; Androgens; Animal Experiments; Antidiabetic Drugs; Antioxidants; Apolipoprotein A-I; Area; Arteries; Arthritis; Atherosclerosis; Attenuated; Autoimmune Diseases; Award; Basic Science; Bile Acids; Biliary; Biochemistry; Biology; Blood Glucose; Body Weight; Cardiovascular Diseases; Cardiovascular system; Caring; Catabolism; Categories; Cells; Central obesity; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Chronic Disease; Cirrhosis; Clinical; Clinical Management; Complex; Development; Diabetes Mellitus; Disease; Dyslipidemias; Endocrinology; Engineering; Fatty Liver; Functional disorder; Funding; Gastrointestinal Physiology; General Population; Genetic Transcription; Glucocorticoids; Goals; Health; Healthcare; Heart; Heart Diseases; Hepatic Tissue; Hepatitis C virus; High Density Lipoproteins; Hormone secretion; Hormones; Human; Huntington Disease; Hydrocortisone; Hyperlipidemia; Hypertension; Hypoglycemic Agents; Hypogonadism; Impairment; Inflammation; Insulin; Insulin Resistance; Journals; Laboratories; Larrea; Link; Lipids; Lipoproteins; Liver; Longitudinal Studies; Low-Density Lipoproteins; Malignant Neoplasms; Mediating; Medical; Metabolic; Metabolic syndrome; Metabolism; Mineralocorticoids; Mission; Mitochondria; Modeling; Molecular; Molecular and Cellular Biology; Muscle; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nordihydroguaiaretic Acid; Obesity; Ovarian; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physiology; Population; Post-Transcriptional Regulation; Pregnenolone; Primary carcinoma of the liver cells; Process; Production; Proteins; Publishing; Rattus; Reactive Oxygen Species; Regulation; Research; Research Activity; Research Personnel; Rodent; Rodent Model; Role; SNAP receptor; SOD2 gene; SR-B proteins; Scientist; Sexual Dysfunction; Spermatogenesis; Steroid biosynthesis; Steroids; Stroke; System; Testosterone; Therapeutic; Tissues; Triglycerides; United States National Academy of Sciences; United States National Institutes of Health; Veterans; Veterans Health Administration; Work; age effect; age related; aging population; career; clinical care; clinical investigation; clinically relevant; comorbidity; dehydroepiandrosterone; diabetic; falls; high density lipoprotein receptor; high density lipoprotein-1; improved; insight; insulin sensitivity; lipid metabolism; lipoprotein cholesterol; men; military veteran; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; oxidative damage; particle; peptidomimetics; peroxiredoxin; receptor; response; reverse cholesterol transport; skeletal tissue; steroid hormone; steroid hormone biosynthesis; uptake

Numerous cross-sectional and longitudinal studies have established that circulating levels of testosterone decline with age in men. Likewise, human aging also results in a gradual decline in ovarian steroid production, a dramatic decline in adrenal androgens (DHEA, DHEAS), and alterations in cortisol and aldosterone production and secretion. Similar to humans, aging in experimental rodents is also associated with profound changes in the synthesis and secretion of steroid hormones, particularly testosterone. For the past 33 years or so (with almost continuous support through Merit Review funding), my laboratory has been actively involved in delineating cellular and molecular mechanisms involved in the age-related decline in steroid hormone biosynthesis and secretion, with a particular emphasis on testosterone. Our work during the past several years has established a causal link between increased reactive oxygen species formation/excessive oxidative stress and oxidative damage to the cellular machinery involved in cholesterol transport to mitochondria resulting in attenuated cholesterol transport with consequent impairment of steroidogenesis during aging. Currently, we are investigating the impact of aging-induced excessive oxidative damage to cytosolic and mitochondrial superoxide dismutase-peroxiredoxin (SOD-PRDX) antioxidant axes on the functional expression of crucial proteins involved in cholesterol transport (SNAREs) to and within the mitochondria (StAR) for the production of steroid precursor, pregnenolone. Over the years, a second major research effort of my laboratory has been and continues to be to understand how cholesterol from lipoproteins, particularly, high-density lipoprotein (HDL), is transported, processed intracellularly, and metabolized by steroidogenic tissues and cells. We are also studying how this process affects steroid hormone synthesis, reverse cholesterol transport (RCT), and atherosclerosis. Our work on HDL metabolism (funded by NIH since 1984), have led to the demonstration that the cellular delivery of HDL-cholesteryl esters (CE) into steroidogenic cells does not involve the endocytic pathway as typified by the LDL (B/E) receptor pathway. Rather, CE is taken into the cell via a `selective' pathway in a process that did not require the internalization of the entire lipoprotein particle. This selective pathway has been extensively characterized by us and it is especially important in liver and steroidogenic tissues where it delivers CE in bulk for product formation (steroid and bile acids) and biliary cholesterol secretion as a part of RCT. Scavenger receptor, class B type 1 (SR-B1) is an HDL receptor that mediates selective delivery of HDL-CEs in steroidogenic and hepatic tissues and is also implicated in the pathophysiology of RCT and atherosclerosis. At present, we are investigating the transcriptional and posttranscriptional regulation of SR-B1 and its relevance to steroidogenesis, RCT, and atherosclerosis. Currently, we are working on two additional projects. One project is focused on defining the lipid lowering and anti-hyperglycemic actions of creosote bush-derived nordihydroguaiaretic acid (NDGA). Previous work from our laboratory has shown that NDGA, has profound effects on the core components of the metabolic syndrome (MetS) including lowering of blood glucose, free fatty acids, and triglyceride (TG) levels in several models of dyslipidemia, as well as improving body weight (obesity), insulin resistance, diabetes, hypertension, and ameliorating hepatic steatosis. The current focus of this project is to elucidate the molecular mechanism by which NDGA exerts its hypolipidemic actions in the major insulin-sensitive tissues, liver, skeletal muscle, and adipose tissue, and improves dyslipidemia, insulin sensitivity and hepatic steatosis. In another project, efficacy of several dual function apoA-I mimetic peptides (Artery Therapeutics, Inc.) engineered to mimic anti- atherosclerotic and anti-diabetic functionalities, is being evaluated using several mouse models atherosclerosis, diabetes, and obesity.

大量的横断面和纵向研究已经证实，循环中的睾酮水平 男性会随着年龄的增长而下降。同样，人类的衰老也会导致卵巢类固醇产量逐渐下降， 肾上腺雄激素(DHEA、DHEAS)急剧下降，皮质醇和醛固酮改变 生产和分泌。与人类相似，实验啮齿动物的衰老也与 类固醇激素，尤其是睾丸素的合成和分泌的变化。在过去的33年或 因此(在功绩评估基金的持续支持下)，我的实验室积极参与了 与年龄相关的类固醇激素下降的细胞和分子机制 生物合成和分泌，特别强调睾丸素。我们过去几年的工作 已经确定了活性氧物种形成增加与过度氧化应激之间的因果联系 以及对参与胆固醇运输到线粒体的细胞机械的氧化损伤，导致 衰老过程中胆固醇转运减弱，导致类固醇合成障碍。目前，我们 正在调查衰老导致的过度氧化损伤对胞浆和线粒体的影响 超氧化物歧化酶-过氧化还蛋白(SOD-PRDX)抗氧化轴对功能表达的重要影响 参与胆固醇转运(SNARs)到线粒体(STAR)和在线粒体(STAR)内的蛋白质，以产生 类固醇前体，孕烯醇酮。多年来，我的实验室的第二项主要研究工作是 并继续了解胆固醇是如何从脂蛋白，特别是高密度脂蛋白 (高密度脂蛋白)由类固醇合成组织和细胞运输、细胞内加工和代谢。我们是 还研究了这一过程如何影响类固醇激素的合成、胆固醇的反向运输(RCT)以及 动脉硬化。我们在高密度脂蛋白代谢方面的工作(自1984年以来由美国国立卫生研究院资助)已经证明 高密度脂蛋白-胆固醇酯(CE)的细胞输送到类固醇生成细胞不涉及内吞 以低密度脂蛋白(B/E)受体途径为代表的途径。相反，CE是通过“选择性”进入细胞的。 该途径不需要整个脂蛋白颗粒的内化。这是有选择性的 途径已经被我们广泛地描述，它在肝脏和类固醇合成中尤其重要 提供大量CE以形成产物(类固醇和胆汁酸)和胆汁胆固醇的组织 分泌物作为随机对照试验的一部分。清道夫受体B类1(SR-B1)是一种高密度脂蛋白受体，介导 在类固醇生成和肝脏组织中选择性递送高密度脂蛋白-CEs，并与 RCT的病理生理学与动脉粥样硬化。目前，我们正在调查转录和 SR-B1的转录后调控及其与类固醇生成、RCT和动脉粥样硬化的相关性。 目前，我们正在进行另外两个项目。一个项目的重点是定义降脂和 杂酚油衍生的去甲二氢愈创木酸(Ndga)的降血糖作用。以前的工作来自 我们的实验室已经证明，NDGA对代谢综合征的核心成分有深远的影响 (METS)，包括降低血糖、游离脂肪酸和甘油三酯(TG)水平 血脂异常，以及改善体重(肥胖)、胰岛素抵抗、糖尿病、高血压和 改善肝脏脂肪变性。本项目目前的重点是通过以下途径来阐明分子机制 NDGA在主要的胰岛素敏感组织、肝脏、骨骼肌和 改善脂肪组织，改善血脂紊乱、胰岛素敏感性和肝脏脂肪变性。在另一个项目中，功效 几种双功能apoA-I模拟肽(动脉治疗公司)被设计成模仿反- 动脉粥样硬化和抗糖尿病的功能正在使用几个小鼠模型进行评估 动脉粥样硬化、糖尿病和肥胖。