BLR&D Research Career Scientist Award application

BLR

• 批准号: 9899084
• 负责人: HUANG-GE ZHANG
• 金额: --
• 依托单位: LOUISVILLE VA MEDICAL MEDICAL CENTER
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899084
• 关键词: 5' -AMP-activated protein kinase; Adipose tissue; Alcoholic liver damage; Antibodies; Award; Biological; Biological Markers; Biology; Brain; Brain Injuries; Brain Neoplasms; Breast Cancer Cell; Broccoli - dietary; Cancer Patient; Caring; Cell Communication; Cell Differentiation Inhibition; Cell Differentiation process; Cells; Cessation of life; Chronic; Clinical; Clinical Management; Colitis; Colon; Colonic Neoplasms; Colorectal; Communication; Curcumin; Cutaneous Melanoma; DNA; Data; Dendritic Cells; Development; Diabetes Mellitus; Dinoprostone; Disease; Disease Progression; Drug Targeting; Edible Plants; Encephalitis; Explosion; Failure; Folic Acid; Food; Foundations; Funding; Gene Expression; Ginger; Goals; Grapefruit; Grapes; Health Status; Hepatocyte; Hepatology; High Fat Diet; Homeostasis; Homing; Human; Immunosuppression; Immunotherapy; Inflammation; Inflammatory; Insulin Resistance; International; Intestines; Journals; Kidney; Light; Link; Lipids; Liver; Long-Term Effects; Lung; Macrophage Activation; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mammalian Cell; Mammary Neoplasms; Manuscripts; Mediating; Medical; Methods; MicroRNAs; Microglia; Molecular; Mucous body substance; Mus; Myelogenous; Myeloid-derived suppressor cells; NK Cell Activation; Names; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oncogenes; Oncogenic; Oncoproteins; Overweight; Patients; Pharmaceutical Preparations; Physiological; Plants; Play; Population; Prostate; Publishing; RNA; Radiation therapy; Research; Resistance; Risk; Role; Scientist; Signal Transduction; Site; Small Interfering RNA; Sorting - Cell Movement; Specificity; T-Lymphocyte; Therapeutic; Therapeutic Agents; Tissues; Traumatic Brain Injury; Tumor Promotion; Tumor Suppressor Proteins; Tumor-Derived; Vesicle; Veterans; WNT Signaling Pathway; War; Work; alcohol prevention; anergy; anticancer research; base; beta catenin; cancer cell; cancer diagnosis; cancer immunotherapy; cancer prevention; cancer therapy; cancer type; career; cell type; chemokine; chemokine receptor; cytokine; dextran sulfate sodium induced colitis; exosome; expression vector; extracellular; folate-binding protein; improved; in vivo; interspecies communication; intestinal homeostasis; liver development; liver inflammation; liver injury; macrophage; major vault protein; member; microvesicles; mild traumatic brain injury; mortality; mouse model; nanoparticle; nanovector; nanovesicle; neoplastic cell; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel strategies; novel therapeutic intervention; nuclear factor-erythroid 2; patient population; pressure; prevent; side effect; sound; stem cells; targeted delivery; therapeutic development; therapeutic miRNA; translational study; treatment strategy; tumor; tumor progression

My research work largely explores the underlying physiologic questions regarding tiny vesicles called exosomes. These exosomes are released from many different types of cells or food-derived exosome-like nanoparticles and I am investigating in VA patients the promising role of exosomes as therapeutic vehicles in delivering treatment for a diverse but specific group of medical conditions, i.e.,obesity/diabetes, Nonalcoholic fatty liver disease (NASH), and cancer. There is a substantial population of veterans who are obese and/or have cancer. Obesity and cancer pose special burdens on veterans who depend on VA care. Obesity contributes to over 300,000 deaths per year and increases the risk of NASH, type 2 diabetes, and several cancers including colon, prostate, and kidney. Since receiving my initial Research Career Scientist award, my research group has published more than 50 manuscripts on this subject. Collectively, our findings support continued funding of my team to investigate the following 3 aims: (1) Tumor exosomes play a role in: (a) immunosuppression through induction of myeloid-derived suppressor cells, inhibition of dendritic cell differentiation, and inhibition of activation of NK cell immunotherapy; (b) by sorting suppressor miRNAs from tumor cells into exosomes based on the oncogenic major vault protein (MVP), tumors grow faster (Nature Communications. 2017 Feb 17;8:14448, Nature communications. 2015;6:6956); and (c) more recently, we discovered a novel nanoparticle (Oncotarget. 2016 May 12). Unlike other EVs, this extracellular nanovesicle (named HG-NV, HG-NV stands for HomoGenous nanovesicle as well as for Huang-Ge- nanovesicle) released from both mouse and human breast tumor cells is enriched with RNAs. Tumor-derived HG-NVs are more potent in promoting tumor progression than exosomes. Molecules predominantly present in breast tumor HG- NVs have been identified and characterized. This discovery may have implications in advancing both microvesicle biology research and clinical management including potential useas a biomarker, (2). Exosomes released from non-tumor cells play a role in: (a) adipose tissue exosome-like vesicles mediating activation of macrophage-induced insulin resistance (Diabetes. 2009 Nov;58(11):2498-505); (b) we also found that intestinal mucus-derived exosomes mediate activation of Wnt/β-catenin signaling and play a role in induction of liver NKT cell anergy (Hepatology, 2013 57(3):1250-61); and (c) intestinal mucus‐derived exosomes carry prostaglandin E2 and suppress activation of liver NKT cells (J Immunol, 2013, 190(7):3579-89); (3). Exosome- like nanoparticles from edible plants have an effect and therapeutic application on mammalian cells: (a) we used mouse models to show that interspecies communication between plant and mouse gut host cells through edible plant derived exosome‐like nanoparticles by inducing expression of genes for anti-inflammation cytokines, antioxidation, and activation of Wnt signaling, which are crucial for maintaining intestinal homeostasis. This finding not only opens up a new avenue for investigating ELNs as a means to protect against the development of liver related diseases such as alcohol induced liver damage, but sheds light on studying the cellular and molecular mechanisms underlying inter-species communication in the liver via edible plant- derived nanoparticles; (b) targeted drug/therapeutic miRNAs (Nature Communications. 2013;4:1867) delivery to intestinal macrophages, brain microglia cells (Molecular therapy: 2015, Volume 24, Issue 1, p96–105) and inflammatory tumor sites (Cancer Research, 2015;75:2520-9) by grapefruit ELN is possible; (c) Broccoli- Derived Nanoparticle Inhibits Mouse Colitis by Activating Dendritic Cell AMP-Activated Protein Kinase (Molecular Therapy. 2017, in press); and (d) Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis (Molecular Therapy. 2013 Jul;21(7):1345-57).

我的研究工作主要是探索与微小囊泡有关的潜在生理学问题 外显体。这些外切体是从许多不同类型的细胞或食物衍生的类似外切体的细胞释放出来的 纳米粒子和我正在研究外切体作为治疗载体在VA患者中的前景 为不同但特定的医疗疾病群体提供治疗，例如肥胖/糖尿病、非酒精性 脂肪肝(NASH)和癌症。有大量的退伍军人患有肥胖症和/或 得了癌症。肥胖和癌症给依赖退伍军人管理局护理的退伍军人带来了特殊的负担。肥胖 每年导致超过300,000人死亡，并增加患NASH、2型糖尿病和几种 癌症包括结肠癌、前列腺癌和肾癌。自从我第一次获得研究职业科学家奖以来，我的 课题组已经发表了50多篇关于这一主题的手稿。总体而言，我们的发现支持 继续资助我的团队调查以下3个目标：(1)肿瘤外切体在以下方面发挥作用：(A) 诱导髓系抑制细胞、抑制树突状细胞的免疫抑制作用 分化和抑制NK细胞免疫治疗的激活；(B)通过从 肿瘤细胞变成外体的基础是致癌的主要拱顶蛋白(MVP)，肿瘤生长得更快(自然 通讯。2017年2月17日；8：14448，自然通讯。2015年；6：6956)；以及(C)最近，我们 发现了一种新的纳米颗粒(OncoTarget.2016年5月12日)。与其他电动汽车不同的是，这种细胞外纳米胶囊 (命名为HG-NV，HG-NV代表均质纳米管和黄歌-纳米管)发布 小鼠和人类乳腺肿瘤细胞中都含有丰富的RNA。肿瘤来源的HG-NV更多 在促进肿瘤进展方面比外切体更有效。主要存在于乳腺肿瘤中的分子HG- NVS已被识别和表征。这一发现可能会对推动这两项工作产生影响 微泡生物学研究和临床管理，包括作为生物标志物的潜在用途，(2)。外切体 从非肿瘤细胞释放的物质在以下方面发挥作用：(A)脂肪组织外胚体样囊泡介导激活 巨噬细胞诱导的胰岛素抵抗(糖尿病。2009年11月；58(11)：2498-505)； 肠粘液来源的外切体介导Wnt/β-连环蛋白信号的激活并在诱导中发挥作用 肝脏NKT细胞无能(肝病学，2013 57(3)：1250-61)；和(C)肠粘液来源的外切体携带 前列腺素E_2和抑制肝脏NKT细胞的激活(《免疫学杂志》，2013,190(7)：3579-89)；外显体- 像来自可食用植物的纳米颗粒一样，对哺乳动物细胞有影响和治疗应用：(A)我们 使用小鼠模型显示植物和小鼠肠道宿主细胞之间的物种间通信通过 通过诱导抗炎基因的表达获得可食用植物来源的外切体样纳米颗粒 细胞因子、抗氧化和Wnt信号的激活对维持肠道至关重要 动态平衡。这一发现不仅为研究ELN作为预防疾病的手段开辟了一条新的途径 与肝脏相关的疾病的发展，如酒精引起的肝损伤，但对研究有启发意义 通过食用植物在肝脏中进行物种间交流的细胞和分子机制-- 衍生纳米粒子；(B)靶向药物/治疗miRNAs(自然通讯。2013年；4：1867)交付 肠巨噬细胞、脑小胶质细胞(分子治疗：2015，第24卷，第1期，第96-105页)和 葡萄柚ELN的炎症肿瘤部位(癌症研究，2015；75：2520-9)是可能的；(C)西兰花- 衍生纳米颗粒通过激活树突状细胞AMP激活的蛋白激酶抑制小鼠结肠炎 (分子疗法。2017)；和(D)葡萄外切体状纳米颗粒诱导肠道干细胞 和保护小鼠免受DSS诱导的结肠炎(分子疗法。2013年7月；21(7)：1345-57)。