BLR&D Research Career Scientist Award application

BLR

• 批准号: 10265394
• 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/10265394
• 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; 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; military veteran; 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).

我的研究工作在很大程度上探讨了有关小蔬菜的潜在生理问题 外泌体。这些外泌体从许多不同类型的细胞或食物衍生的外泌体样本释放 纳米颗粒和我正在调查VA患者的外泌体作为治疗载体的有前途的作用 提供多样性但特定的医疗状况的治疗，即肥胖/糖尿病，非酒精 脂肪肝病（NASH）和癌症。肥胖和/或 患有癌症。肥胖和癌症对依赖VA护理的退伍军人构成了特殊的伯伦斯。肥胖 每年造成300,000多人死亡，并增加了NASH，2型糖尿病的风险，有几种 包括结肠，前列腺和肾脏在内的癌症。自从获得我最初的研究职业科学家奖以来 研究小组已经发表了50多种有关该主题的手稿。总的来说，我们的发现支持 我的团队继续资金调查以下3个目标：（1）肿瘤外泌体在：（a）中发挥作用 免疫抑制通过诱导髓样衍生的抑制细胞，抑制树突细胞 分化和抑制NK细胞免疫疗法的激活； （b）从中排序抑制器miRNA 肿瘤细胞基于致癌主要保力蛋白（MVP），肿瘤生长速度更快（自然 通讯。 2017年2月17日； 8：14448，自然通讯。 2015; 6：6956）; （c）最近，我们 发现了一种新颖的纳米颗粒（Oncotarget。20165月12日）。与其他电动汽车不同，该细胞外纳米层 （命名为HG-NV，HG-NV代表同质纳米层以及黄纳维亚的纳米层）释放 来自小鼠和人类乳腺肿瘤细胞均富含RNA。肿瘤来源的HG-NV更多 促进肿瘤进展的有效性比外泌体。分子主要存在于乳腺肿瘤Hg- NV已被识别和表征。这一发现可能对提升两者有影响 微丝生物学研究和临床管理，包括潜在的生物标志物，（2）。外泌体 从非肿瘤细胞释放起来在以下角色中发挥作用：（a）脂肪组织外泌体样蔬菜，介导的激活 巨噬细胞诱导的胰岛素抵抗（糖尿病，2009年11月； 58（11）：2498-505）； （b）我们还发现 Wnt/β-catenin信号传导的肠道粘液衍生的外泌体培养基激活并在诱导中起作用 肝脏NKT细胞消极（Hepatology，2013 57（3）：1250-61）; （c）肠粘膜衍生的外泌体携带 前列腺素E2和抑制肝NKT细胞的激活（J Immunol，2013，190（7）：3579-89）; （3）。外泌体 像来自食用植物的纳米颗粒一样，对哺乳动物细胞具有影响和治疗应用：（a）我们 使用的鼠标模型表明植物和鼠标肠道宿主细胞之间的种间通信通过 可食用的植物通过诱导基因表达抗炎而衍生的外泌体样纳米颗粒 Wnt信号传导的细胞因子，抗氧化和激活，这对于维持肠道至关重要 稳态。这一发现不仅为调查ELN的新途径开辟了一条新的途径 肝脏相关疾病（例如酒精引起的肝脏损害）的发展，但阐明了研究 肝之间通过可食用植物 - 派生的纳米颗粒； （b）有针对性的药物/治疗性miRNA（自然通讯，2013; 4：1867）交付 对于肠道巨噬细胞，脑小胶质细胞（分子治疗：2015，第24卷，第1期，P96–105）和 葡萄柚ELN的炎症肿瘤部位（癌症研究，2015年； 75：2520-9）是可能的； （c）boccoli- 衍生的纳米颗粒通过激活树突状细胞AMP激活的蛋白激酶来抑制小鼠结肠炎 （分子疗法。2017年，印刷中）； （d）葡萄外泌体样纳米颗粒诱导肠道干细胞 并保护小鼠免受DSS诱导的结肠炎（MolecularTherapy。2013Jul; 21（7）：1345-57）。