BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10265407
• 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/10265407
• 关键词: Address; Adipose tissue; Adrenal Glands; Affect; Age; Aging; Alcohol abuse; Aldosterone; Alzheimer' s Disease; American; Amyotrophic Lateral Sclerosis; Androgens; Animals; Antidiabetic Drugs; Antioxidants; Apolipoprotein A-I; 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; Cross-Sectional Studies; Development; Diabetes Mellitus; Disease; Dyslipidemias; Endocrinology; Engineering; Fatty Liver; Functional disorder; Funding; Gastrointestinal Physiology; General Population; 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; Lead; 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; 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; Skeletal Muscle; Spermatogenesis; Steroid biosynthesis; Steroids; Stroke; System; Testosterone; Therapeutic; Tissues; Transcriptional Regulation; Transport Process; 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; high density lipoprotein receptor; 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; scavenger receptor; 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.

大量的横截面和纵向研究已经确定睾丸激素的循环水平 随着男性年龄的增长。同样，人类衰老也导致卵巢类固醇产生的逐渐下降， 肾上腺雄激素（DHEA，DHEAS）以及皮质醇和醛固酮改变的急剧下降 生产和分泌。与人类类似，实验啮齿动物的衰老也与深度有关 类固醇激素的合成和分泌的变化，尤其是睾丸激素。在过去的33年中， 因此（（几乎通过优异审查资金提供了几乎不断的支持），我的实验室一直积极参与 描述与年龄相关类固醇激素下降的细胞和分子机制 生物合成和分泌，特别着重于睾丸激素。我们过去几年的工作 已经建立了活性氧形成/过度氧化应激之间的因果关系 以及对胆固醇转运到线粒体涉及的细胞机械的氧化损伤，导致 减弱胆固醇的转运，因此在衰老过程中损害了类固醇生成。目前，我们 正在研究衰老诱导的过度氧化损伤对胞质和线粒体的影响 在关键的功能表达上 参与线粒体（星形）的胆固醇运输（SNARE）的蛋白质用于生产 类固醇前体，妊娠。多年来，我的实验室的第二项主要研究工作是 并继续了解脂蛋白的胆固醇如何，尤其是高密度脂蛋白 （HDL），被转运，细胞内处理，并被类固醇生成组织和细胞代谢。我们是 还研究该过程如何影响类固醇激素的合成，反向胆固醇转运（RCT）和 动脉粥样硬化。我们关于HDL代谢的工作（自1984年以来由NIH资助），导致了这样的证明 HDL-色酸酯（CE）向类固醇生成细胞的细胞递送不涉及内吞 途径为LDL（B/E）受体途径。而是通过“选择性”将CE带入单元 在不需要整个脂蛋白颗粒内部化的过程中的途径。这个选择性 途径已被我们广泛特征，它在肝脏和类固醇中尤为重要 它批量提供产品形成的组织（类固醇和胆汁酸）和胆汁胆固醇 分泌作为RCT的一部分。清道夫受体，B类1（SR-B1）是介导的HDL受体 在类固醇和肝组织中选择性递送HDL-CE，也与 RCT和动脉粥样硬化的病理生理。目前，我们正在研究转录和 SR-B1的转录后调节及其与类固醇生成，RCT和动脉粥样硬化的相关性。 目前，我们正在研究其他两个项目。一个项目的重点是定义脂质降低和 克里索灌木丛衍生的北多糖酸（NDGA）的抗血糖作用。以前的工作 我们的实验室表明，NDGA对代谢综合征的核心成分具有深远的影响 （MetS）包括降低血糖，游离脂肪酸和甘油三酸酯（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 改善肝脂肪变性。该项目的当前重点是通过 NDGA在主要胰岛素敏感的组织，肝脏，骨骼肌和 脂肪组织，改善血脂异常，胰岛素敏感性和肝脂肪变性。在另一个项目中，功效 在模仿抗抗抗菌的几种双功能ApoA-I模拟肽（动脉疗法，Inc。）中 动脉粥样硬化和抗糖尿病功能正在使用几种小鼠模型进行评估 动脉粥样硬化，糖尿病和肥胖。