BLR&D Research Career Scientist Award application

BLR

• 批准号: 10454206
• 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/10454206
• 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; 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; 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; 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; delivery vehicle; 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; military veteran; mortality; mouse model; murine colitis; 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).

我的研究工作主要探索有关微小囊泡的潜在生理问题 外泌体。这些外泌体由许多不同类型的细胞或食物来源的外泌体样释放 纳米颗粒，我正在 VA 患者中研究外泌体作为治疗载体的有希望的作用 为多种但特定的医疗状况提供治疗，即肥胖/糖尿病、非酒精性 脂肪肝疾病（NASH）和癌症。有大量的退伍军人患有肥胖和/或 患有癌症。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 NASH、2 型糖尿病和多种疾病的风险 癌症，包括结肠癌、前列腺癌和肾癌。自从获得我最初的研究职业科学家奖以来，我 研究小组就此课题发表了50多篇论文。总的来说，我们的研究结果支持 继续资助我的团队研究以下 3 个目标：(1) 肿瘤外泌体在以下方面发挥作用：(a) 通过诱导骨髓源性抑制细胞、抑制树突状细胞来抑制免疫 NK细胞免疫疗法的分化和激活抑制； (b) 通过分选抑制 miRNA 将肿瘤细胞转化为基于致癌主要穹窿蛋白（MVP）的外泌体，肿瘤生长得更快（Nature 通讯。 2017 年 2 月 17 日；8:14448，自然通讯。 2015;6:6956); (c) 最近，我们 发现了一种新型纳米颗粒（Oncotarget。2016 年 5 月 12 日）。与其他电动汽车不同，这种细胞外纳米囊泡 （命名为HG-NV，HG-NV代表HomoGenous nanovesicle以及Huang-Ge-nanovesicle）发布 来自小鼠和人类乳腺肿瘤细胞的RNA富含RNA。肿瘤来源的 HG-NVs 更多 比外泌体更能有效促进肿瘤进展。主要存在于乳腺肿瘤 HG- 中的分子 NV 已被识别和表征。这一发现可能对推进两者都有影响 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)。外泌体 非肿瘤细胞释放的外泌体样囊泡在以下方面发挥作用：（a）介导脂肪组织外泌体样囊泡的激活 巨噬细胞诱导的胰岛素抵抗（Diabetes。2009年11月；58（11）：2498-505）； (b) 我们还发现 肠粘液来源的外泌体介导 Wnt/β-连环蛋白信号传导的激活并在诱导中发挥作用 肝脏NKT细胞无反应性的影响(Hepatology, 2013 57(3):1250-61); (c) 肠粘液衍生的外泌体携带 前列腺素 E2 并抑制肝脏 NKT 细胞的活化 (JImmunol, 2013, 190(7):3579-89)； （3）。外泌体- 来自可食用植物的纳米颗粒对哺乳动物细胞有影响和治疗应用：（a）我们 使用小鼠模型表明植物和小鼠肠道宿主细胞之间的种间通讯通过 通过诱导抗炎基因表达来制备可食用植物来源的外泌体样纳米颗粒 细胞因子、抗氧化和 Wnt 信号传导的激活，这些对于维持肠道至关重要 体内平衡。这一发现不仅为调查 ELN 作为防范手段开辟了新途径 肝脏相关疾病的发展，例如酒精引起的肝损伤，但对研究有启发 通过食用植物在肝脏中进行物种间通讯的细胞和分子机制 衍生的纳米颗粒； (b) 靶向药物/治疗性 miRNA (Nature Communications. 2013;4:1867) 递送 肠道巨噬细胞、脑小胶质细胞（分子治疗：2015 年，第 24 卷，第 1 期，第 96-105 页）和 葡萄柚 ELN 可以检测炎症性肿瘤部位（Cancer Research，2015；75：2520-9）； (c) 西兰花- 衍生纳米颗粒通过激活树突状细胞 AMP 激活蛋白激酶抑制小鼠结肠炎 （分子疗法。2017 年，待出版）； (d) 葡萄外泌体样纳米粒子诱导肠道干细胞 并保护小鼠免受 DSS 诱导的结肠炎（Molecular Therapy. 2013 Jul;21(7):1345-57）。