BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10337062
• 负责人: Rhonda D Kineman
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337062
• 关键词: Acromegaly; Adipose tissue; Adult; Age; Animals; Anterior Pituitary Gland; Area; Aryl Hydrocarbon Receptor; Award; Biochemical; Birth; Book Chapters; Cardiovascular Diseases; Cells; Chicago; Citric Acid Cycle; Clinical; Clinical Research; Closure by clamp; Collaborations; Complement Factor H; Cues; Data; Development; Diabetes Mellitus; Diet; Dietary Fatty Acid; Disease; Disease Progression; Doctor of Philosophy; Dopamine Receptor; Drug Targeting; Endocrinology; Enterobacteria phage P1 Cre recombinase; Enzymes; Estrogen Receptors; Etiology; Faculty; Fasting; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Feedback; Fibrosis; Foundations; Funding; Future; Gene Expression; Gene Proteins; General Population; Genes; Glucose Clamp; Glycolysis; Grant Review; Growth; Growth Hormone Receptor; Growth Hormone Secreting Pituitary Neoplasm; Growth Hormone Signaling Pathway; Guanine + Cytosine Composition; Health; Hepatic; Hepatocyte; Hormone secretion; Human; Hydrocarbons; Hyperglycemia; Hyperinsulinism; Hypothalamic structure; Illinois; Impairment; Inflammation; Injury; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Internet; Investigation; JAK2 gene; Journals; Knock-out; Laboratories; Lactation; Leadership; Lipolysis; Liver; Malignant neoplasm of liver; Manuscripts; Mass Fragmentography; Mediating; Medical center; Medicine; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Mutation; Neuroendocrinology; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Pattern; Peer Review; Physiology; Pituitary Gland; Pituitary Hormones; Plasma; Production; Proteins; Puberty; Publishing; Receptor Signaling; Reporting; Reproduction; Research; Research Personnel; Risk; Role; Science; Scientist; Seminal; Services; Severities; Signal Pathway; Signal Transduction; Societies; Solid; Somatostatin Receptor; Somatotrope Cell; Somatotrophin increased; Somatotropin; Speed; Thyroxine-Binding Globulin; Time; Tissues; Toxic Environmental Substances; Tracer; United States National Institutes of Health; Universities; Veterans; Weight Gain; Work; adeno-associated viral vector; base; career; combat veteran; comorbidity; delivery vehicle; diabetic; diabetic patient; diabetic wound healing; editorial; experimental study; extracellular; glucose production; growth hormone deficiency; hormonal signals; hormone resistance; improved; injury and repair; insulin sensitivity; leptin receptor; lipid biosynthesis; liver injury; liver transplantation; meetings; member; metabolic phenotype; military veteran; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; obese patients; post-doctoral training; prevent; promoter; protective effect; protein expression; receptor; reconstitution; repaired; repository; stable isotope; therapy development; tissue injury; tool; transgene delivery; treatment response; treatment strategy; tumor; tumor progression; vibration; wound healing

The overarching theme of my current research is to understand how growth hormone (GH) and insulin-like growth factor I (IGF1) regulate adult metabolic function and how dysregulation of GH/IGF1 production and signaling contributes to the progression of metabolic disease, as well as related tissue injury and repair. A major focus of my work is to understand the etiology of non-alcoholic fatty liver disease (NAFLD). NAFLD represents a spectrum of excess fat accumulation in the liver (steatosis) without or with inflammation/fibrosis (non-alcoholic steatohepatitis - NASH). NAFLD is commonly observed in obesity and type 2 diabetes, but is also observed in non-obese patients associated with cardiovascular disease, where all diseases are more prevalent in Veterans, compared to the general population. NASH increases the risk of developing liver cancer, and is now recognized as the leading cause for liver transplantation. Dietary fatty acids (FA) and FA derived from adipose tissue lipolysis, due to systemic insulin resistance, are major contributors to NAFLD. In addition, enhanced hepatic de novo lipogenesis (DNL) contributes to NAFLD. Clinical and experimental studies show NAFLD is associated with reduced GH-signaling (reflected by low plasma GH and hepatic GH resistance, leading to low IGF1 levels). The reduction in GH-signaling may exacerbate NAFLD, based on studies showing SNPs within the GH / GH receptor (GHR) /JAK2 / Stat5 signaling pathway are associated with NAFLD. Also, increasing GH can reduce NAFLD in both humans and mice. We have reported that adult-onset loss of hepatocyte GH signaling (aHepGHRkd; GHRfl/fl mice treated with an adeno-associated viral vector expressing thyroxine binding globulin promoter driven Cre [AAV8-TBGp-Cre]) led to the rapid development of steatosis, associated with an increase in DNL (Cordoba-Chacon et al., Diabetes 2015). Of translational relevance, hepatic DNL/steatosis after aHepGHRkd is sustained with age and associated with hepatocyte ballooning, inflammation and fibrosis (hallmarks of NASH; Cordoba-Chacon et al., Endocrinology 2018). Studies outlined in my current R01 take a multi-level approach to define the biochemical/molecular mechanisms by which hepatocyte GH-signaling directly controls glycolysis-driven DNL and steatosis, by manipulating hepatocyte GH signaling in mice by hepatocyte-specific, AAV-vector delivery of transgenes within the GH-signaling pathway then assessing; gene and protein expression of enzymes in glycolytic and lipogenic pathways, fatty acid composition by GC/MS, glycolytic flux and TCA cycle intermediates under hyperinsulinemic:hyperglycemic clamps, using stable isotope tracers. Studies outlined in my current BL&RD VA Merit are focused how the reduction in hepatocyte GH signaling contributes to diet-induced NASH and how reconstitution of the GHR signaling pathway (specifically Stat5b activity and/or IGF1 using AAV vector delivery) may prevent and/or reverse steatosis and liver injury. To date we have exciting preliminary data suggesting, hepatocyte GH-signaling works independently of Stat5b/IGF1 to suppress hepatic DNL, while Stat5b is critical to protect the liver from diet-induced injury. These protective effects may extend to other types of liver injury including those induced by environmental toxins (focus of CACHET pilot award). In addition to assessing the role of GH/IGF1 in protecting the liver from injury, in collaboration with Timothy Koh, PhD (UIC, wound healing expert) we are exploring the role of IGF1 in regulating diabetic wound healing. These studies are funded by a RR&D VA Merit and examine the basic mechanisms of wound healing in mouse models of insulin-resistance (diet-induced) and diabetes (db/db) with or without hepatic IGF1 production. Studies will also examine if low-intensity vibration patches (developed and optimized by Onur Bilgen PhD, Rutgers) can speed wound healing via enhanced IGF1 production/actions. Taken together, these basic studies will help to identify unique targets that can be used to develop treatment strategies, in order to prevent the deleterious consequences of obesity/diabetes, which are commonly found in the Veteran population.

我目前研究的首要主题是了解生长激素（GH）和胰岛素样 生长因子I（IGF1）调节成人代谢功能，以及GH/IGF1产生和 信号传导有助于代谢疾病的进展以及相关的组织损伤和修复。一个主要 我的工作重点是了解非酒精性脂肪性肝病（NAFLD）的病因。NAFLD代表 肝脏中一系列过量脂肪积聚（脂肪变性），不伴有或伴有炎症/纤维化（非酒精性 脂肪性肝炎-NASH）。NAFLD通常在肥胖和2型糖尿病中观察到，但也在肥胖和2型糖尿病中观察到。 与心血管疾病相关的非肥胖患者，其中所有疾病在退伍军人中更普遍， 与一般人群相比。NASH增加了患肝癌的风险，现在已经被认识到 是肝移植的主要原因。膳食脂肪酸（FA）和脂肪组织来源的FA 由于全身性胰岛素抵抗引起的脂肪分解是NAFLD的主要原因。此外，增强的肝硬化 新生脂肪生成（DNL）导致NAFLD。临床和实验研究表明，NAFLD与 GH信号传导减少（反映为低血浆GH和肝GH抵抗，导致低IGF 1水平）。的 GH信号的减少可能会加剧NAFLD，基于研究显示GH/GH受体内的SNP (GHR)/JAK2/Stat5信号通路与NAFLD相关。此外，增加GH可以减少NAFLD， 人类和老鼠都是。 我们已经报道了成年期肝细胞GH信号转导的丢失（aHepGHRkd; GHRfl/fl小鼠用一种 表达甲状腺素结合球蛋白启动子驱动的Cre [AAV8-TBGp-Cre]的腺相关病毒载体） 与DNL增加相关的脂肪变性的快速发展（Cordoba-Chacon等，糖尿病 2015年）的报告。翻译相关性，aHepGHRkd后肝DNL/脂肪变性随着年龄的增长而持续， 肝细胞气球样变、炎症和纤维化（NASH的标志; Cordoba-Chacon等人， Endocrinology 2018）。在我目前的R01中概述的研究采取多层次的方法来定义 肝细胞GH信号直接控制糖酵解驱动的DNL的生化/分子机制 和脂肪变性，通过肝细胞特异性的AAV载体递送来操纵小鼠中的肝细胞GH信号传导， GH信号通路内的转基因，然后评估; 糖酵解和脂肪生成途径，GC/MS脂肪酸组成，糖酵解通量和TCA循环中间体 在高胰岛素血症下：高血糖钳夹，使用稳定同位素示踪剂。在我目前的研究中， BL & RD VA Merit专注于肝细胞GH信号传导的减少如何促成饮食诱导的NASH 以及如何使用AAV载体重建GHR信号传导途径（特别是Stat5b活性和/或IGF 1 递送）可以预防和/或逆转脂肪变性和肝损伤。到目前为止，我们有令人兴奋的初步数据， 提示肝细胞GH信号独立于Stat5b/IGF 1抑制肝DNL，而Stat5b/IGF 1抑制肝DNL， 对保护肝脏免受饮食引起的损伤至关重要。这些保护作用可能会扩展到其他类型的肝脏 伤害，包括环境毒素引起的伤害（CACHET试点奖的重点）。 除了评估GH/IGF 1在保护肝脏免受损伤中的作用外， Koh博士（UIC，伤口愈合专家）我们正在探索IGF 1在调节糖尿病伤口愈合中的作用。 这些研究由RR & D VA Merit资助，并检查了小鼠伤口愈合的基本机制。 胰岛素抵抗（饮食诱导）和糖尿病（db/db）模型，伴或不伴肝IGF 1产生。研究 还将研究低强度振动补丁（由罗格斯大学Onur Bilgen博士开发和优化）是否可以 通过增强IGF1的产生/作用加速伤口愈合。这些基础研究将有助于 确定可用于制定治疗策略的独特靶点，以防止有害的 肥胖/糖尿病的后果，这是常见于退伍军人群体。