BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10514612
• 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/10514612
• 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; Exclusion; Faculty; Fasting; Fatty Acids; 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; 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; 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; 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; Tissues; Toxic Environmental Substances; Tracer; United States National Institutes of Health; Universities; Veterans; Weight Gain; Work; adeno-associated viral vector; 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; 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; reconstitution; repaired; repository; stable isotope; therapy development; tissue injury; tissue repair; 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.

我当前研究的首要主题是了解生长激素 (GH) 和胰岛素样药物如何 生长因子 I (IGF1) 调节成人代谢功能以及 GH/IGF1 产生和调节失调如何 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。一个专业 我的工作重点是了解非酒精性脂肪肝病 (NAFLD) 的病因。 NAFLD代表 肝脏中一系列过量脂肪堆积（脂肪变性），无或伴有炎症/纤维化（非酒精性 脂肪性肝炎 - NASH）。 NAFLD 常见于肥胖和 2 型糖尿病，但也见于 与心血管疾病相关的非肥胖患者，所有疾病在退伍军人中更为普遍， 与一般人群相比。 NASH 会增加患肝癌的风险，现已得到认可 成为肝移植的主要原因。膳食脂肪酸 (FA) 和源自脂肪组织的 FA 全身胰岛素抵抗导致的脂肪分解是 NAFLD 的主要原因。此外，增强肝功能 新脂肪生成 (DNL) 会导致 NAFLD。临床和实验研究表明 NAFLD 与 GH 信号传导减弱（表现为低血浆 GH 和肝脏 GH 抵抗，导致 IGF1 水平低）。这 根据研究显示 GH / GH 受体内的 SNP，GH 信号传导的减少可能会加剧 NAFLD (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。 我们已经报道，成年发病的肝细胞 GH 信号传导丧失（aHepGHRkd；GHRfl/fl 小鼠用 表达甲状腺素结合球蛋白启动子驱动的腺相关病毒载体 Cre [AAV8-TBGp-Cre]) 主导 与 DNL 增加相关的脂肪变性的快速发展（Cordoba-Chacon 等人，糖尿病 2015）。具有转化相关性的是，aHepGHRkd 后的肝脏 DNL/脂肪变性随着年龄的增长而持续，并且相关 伴有肝细胞膨胀、炎症和纤维化（NASH 的标志；Cordoba-Chacon 等人， 内分泌学2018）。我当前的 R01 中概述的研究采用多层次方法来定义 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 载体传递来操纵小鼠的肝细胞 GH 信号传导 GH 信号通路内的转基因，然后进行评估；酶的基因和蛋白质表达 糖酵解和脂肪生成途径、GC/MS 测定的脂肪酸组成、糖酵解通量和 TCA 循环中间体 高胰岛素血症：高血糖钳夹，使用稳定同位素示踪剂。我当前概述的研究 BL&RD VA Merit 重点关注肝细胞 GH 信号传导的减少如何导致饮食诱发的 NASH 以及如何使用 AAV 载体重建 GHR 信号通路（特别是 Stat5b 活性和/或 IGF1） 分娩）可以预防和/或逆转脂肪变性和肝损伤。迄今为止，我们有令人兴奋的初步数据 这表明，肝细胞 GH 信号传导独立于 Stat5b/IGF1 来抑制肝脏 DNL，而 Stat5b 对于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，包括由环境毒素引起的伤害（CACHET 试点奖的重点）。 除了评估 GH/IGF1 在保护肝脏免受损伤方面的作用外，还与 Timothy 合作 Koh 博士（UIC，伤口愈合专家）我们正在探索 IGF1 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，研究小鼠伤口愈合的基本机制 有或没有肝脏 IGF1 产生的胰岛素抵抗（饮食诱导）和糖尿病 (db/db) 模型。研究 还将检查低强度振动贴片（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/作用来加速伤口愈合。总的来说，这些基础研究将有助于 确定可用于制定治疗策略的独特目标，以防止有害的疾病发生 肥胖/糖尿病的后果，这在退伍军人群体中很常见。