BLR&D Research Career Scientist Award Application

BLR

• 批准号: 9899086
• 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/9899086
• 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; 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; Work; age effect; age related; aging population; career; clinical care; clinical investigation; clinically relevant; comorbidity; dehydroepiandrosterone; diabetic; health administration; high density lipoprotein receptor; improved; insight; insulin sensitivity; lipid metabolism; lipoprotein cholesterol; men; 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.

大量横断面和纵向研究已证实睾酮的循环水平 男性随着年龄的增长而下降。同样，人类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，皮质醇和醛固酮发生变化 产生和分泌。与人类类似，实验啮齿动物的衰老也与深刻的 类固醇激素，特别是睾酮的合成和分泌发生变化。过去 33 年或 因此（通过优异评审资金几乎持续提供支持），我的实验室一直积极参与 描绘与年龄相关的类固醇激素下降所涉及的细胞和分子机制 生物合成和分泌，特别强调睾酮。我们这几年的工作 已建立活性氧形成增加/过度氧化应激之间的因果关系 以及对参与胆固醇转运至线粒体的细胞机制的氧化损伤，导致 胆固醇转运减弱，从而导致衰老过程中类固醇​​生成受损。目前，我们 正在研究衰老引起的过度氧化损伤对细胞质和线粒体的影响 超氧化物歧化酶-过氧化还原蛋白（SOD-PRDX）抗氧化轴对关键功能表达的影响 参与胆固醇转运 (SNARE) 到线粒体 (StAR) 以及线粒体内 (StAR) 的蛋白质，用于产生 类固醇前体，孕烯醇酮。多年来，我实验室的第二项主要研究工作是 并继续了解脂蛋白，特别是高密度脂蛋白中的胆固醇如何 (HDL)，在细胞内运输、加工，并由生成类固醇的组织和细胞代谢。我们是 还研究这个过程如何影响类固醇激素合成、逆转胆固醇转运 (RCT) 和 动脉粥样硬化。我们在 HDL 代谢方面的工作（自 1984 年起由 NIH 资助）已证明： HDL-胆固醇酯 (CE) 向类固醇生成细胞的细胞递送不涉及内吞作用 以 LDL (B/E) 受体途径为代表的途径。相反，CE 通过“选择性”进入细胞 该过程不需要整个脂蛋白颗粒的内化。这种选择性的 我们已经广泛表征了该途径，它在肝脏和类固醇生成中尤其重要 组织中大量输送 CE 以形成产物（类固醇和胆汁酸）和胆汁胆固醇 分泌作为随机对照试验的一部分。清道夫受体，B 型 1 型 (SR-B1) 是一种 HDL 受体，可介导 HDL-CE 在类固醇生成组织和肝组织中的选择性递送，也与 RCT 和动脉粥样硬化的病理生理学。目前，我们正在研究转录和 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，我们正在开展另外两个项目。一个项目的重点是定义降脂和 杂酚油灌木衍生的去甲二氢愈创木酸（NDGA）的抗高血糖作用。之前的作品来自 我们的实验室已证明 NDGA 对代谢综合征的核心组成部分具有深远的影响 (MetS) 包括降低几种模型中的血糖、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。该项目目前的重点是通过以下方式阐明其分子机制： NDGA 在主要的胰岛素敏感组织、肝脏、骨骼肌和 脂肪组织，并改善血脂异常、胰岛素敏感性和肝脂肪变性。在另一个项目中，功效 几种双功能 apoA-I 模拟肽（Artery Therapeutics, Inc.）设计用于模拟抗 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。