BLR&D Research Career Scientist Award

BLR

• 批准号: 10454100
• 负责人: Heather L Francis
• 金额: --
• 依托单位: RLR 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: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454100
• 关键词: Abdominal Pain; Aging; American; Antihistamines; Area; Award; Bile Acids; Bile fluid; Biliary; Biological Markers; Cell Count; Cells; Cellular biology; Chemotactic Factors; Cholangiocarcinoma; Cholestasis; Chronic; Cicatrix; Cirrhosis; Clinical; Collaborations; Colorectal Cancer; Cromolyn Sodium; Data; Development; Diagnosis; Disease; Disease Progression; Epithelial; Fibrosis; Functional disorder; Funding; Gall Bladder Diseases; Gallbladder; Gallbladder Carcinoma; Gastroenterology; Genetic; Goals; Grant; Healthcare Systems; Hepatic; Hepatic Stellate Cell; Hepatobiliary; Hepatocyte; Hepatology; Heterogeneity; High Fat Diet; Histamine; Histamine Receptor; Icterus; Immune system; In Vitro; Incidence; Indiana; Inflammation; Inflammatory Bowel Diseases; Injury; Internal Medicine; International; Investigation; Journals; K-Series Research Career Programs; Knockout Mice; Laboratories; Left; Leptin; Ligation; Link; Liver; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Manuscripts; Mediator of activation protein; Medical Students; Medical center; Medicine; Mentors; Mesenchymal; Mission; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neurosecretory Systems; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Postdoctoral Fellow; Preparation; Progressive Disease; Pruritus; Publications; Publishing; Reaction; Recurrence; Research; Research Personnel; Research Support; Risk; Rodent; Rodent Model; Role; Scientist; Seminal; Signal Pathway; Signal Transduction; Study Section; Symptoms; Texas; Time; Training; Transforming Growth Factor beta; Transplantation; Tumor Angiogenesis; Ulcerative Colitis; United States; United States National Institutes of Health; Universities; Veterans; Work; angiogenesis; autocrine; bile duct; biliary tract; career; cell motility; cell transformation; cell type; cholangiocyte; editorial; graduate student; gut microbiota; high risk; human model; in vivo; interest; liver injury; liver transplantation; mast cell; member; migration; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; patient population; post-doctoral training; primary sclerosing cholangitis; programs; receptor; recruit; reduce symptoms; release factor; senescence; senior faculty; symposium; therapeutic target; treatment strategy; tumor; tumor growth; tumor progression; undergraduate student

AIMS: The goal of this application is to apply for Research Career Scientist (RCS) Award and to support Dr. Heather Francis’ VA research program. NOMINEE: The candidate, Dr. Heather Francis, is the Scientific Director of the inaugural Indiana Center for Liver Research (ICLR) at Richard L. Roudebush VA Medical Center in Indianapolis as well as a full Professor of Medicine in the Department of Internal Medicine, Division of Gastroenterology and Hepatology at Indiana University. Dr. Francis recently assumed this position in January of 2019 and continues her VA funded work in Indianapolis. Prior to moving to Indiana, Dr. Francis was a Research Biologist at Central Texas Veteran’s Health Care System in Temple, Texas and she has had continuous VA funding since 2012 with the inception of a VA Career Development Award which she transitioned into a BLRD VA Merit Award in 2016. Dr. Francis’ area of interest and expertise lies in the pathophysiology of cholangiocyte (bile duct cells) biology and Dr. Francis has been trained and mentored by a world-renowned expert, Dr. Gianfranco Alpini (2007 – 2015). Dr. Francis has become a leader in the field of hepatic mast cells and their contribution to liver diseases and also how mast cells interact with resident liver cells, including cholangiocytes and hepatic stellate cells. Currently, Dr. Francis holds a BLRD VA Merit (resubmitted and scored, June 2019) and two NIH NIDDK R01 awards (role: PI on both). She serves as a permanent member on the NIH NIDDK Hepatobiliary Pathophysiology Study Section (2018- 2023) and is on the editorial board of Hepatology, Laboratory Investigation and PLoSOne. Dr. Francis has been an active mentor since 2011 and continues to serve on graduate student committees, train post-doctoral fellows and develop collaborations with clinical partners. In addition, since 2012, Dr. Francis has maintained a number of collaborations with VA funded investigators that has resulted in numerous publications. IMPACT: Primary Sclerosing Cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts which normally allow bile to drain from the gallbladder. Patients who suffer from PSC may be asymptomatic or suffer from a myriad of symptoms such as jaundice, itching and abdominal pain. In addition, most patients with PSC (upwards of 75%) also suffer from inflammatory bowel diseases like Ulcerative Colitis, thus complicating their treatment strategies. The risks of PSC include increased incidences of CCA, but also colorectal cancer and gallbladder carcinoma are found in more patients with PSC then without. The causes of PSC are not fully known; however, some studies point to genetic links, malfunctioning immune systems and a dysregulation of the gut microbiota. Treatment options for patients with PSC are severely limited. There is a sub-population of patients who get relief from treatment with the bile acid, ursodeoxycholate; however, not all patients respond. Liver transplantation remains the most definitive “cure” or treatment for PSC, but there is a chance of recurrence following transplantation. The estimated survival time from diagnosis is ~20 years depending upon the stage of discovery and management throughout. Our work has demonstrated that histamine (derived primarily from mast cells) levels are increased in patients with PSC and patients with CCA. In addition, we have shown that mast cell numbers increase in these patients and are found close to bile ducts, thus making this work highly clinically important. This proposal aims to identify biomarkers and potential novel therapies to both alleviate symptoms and offer curative advances without transplantation. In addition, since PSC can develop into CCA (which is increased in a subpopulation of U.S. Veterans), we will also aim to understand the transition of PSC and signaling mechanisms that regulate this development of CCA.

目的：本申请的目的是申请研究职业科学家（RCS）奖并支持 Dr. 希瑟·弗朗西斯的退伍军人事务部研究计划。 提名人： 候选人希瑟·弗朗西斯 (Heather Francis) 博士是首届印第安纳肝脏中心的科学主任 印第安纳波利斯 Richard L. Roudebush VA 医疗中心的研究 (ICLR)，同时也是该学院的正教授 印第安纳州内科、胃肠病学和肝病科医学 大学。弗朗西斯博士最近于 2019 年 1 月担任此职位，并继续她在 VA 资助的工作 印第安纳波利斯。在搬到印第安纳州之前，弗朗西斯博士是德克萨斯州中部退伍军人健康中心的研究生物学家 德克萨斯州坦普尔的护理系统，自 2012 年 VA 成立以来，她一直持续获得 VA 资助 职业发展奖，她于 2016 年转变为 BLRD VA 优异奖。Francis 博士的领域 弗朗西斯博士的兴趣和专业知识在于胆管细胞（胆管细胞）生物学的病理生理学， 接受了世界知名专家 Gianfranco Alpini 博士（2007 – 2015）的培训和指导。弗朗西斯博士有 成为肝肥大细胞领域的领导者及其对肝脏疾病的贡献以及肥大细胞如何 与驻留肝细胞相互作用，包括胆管细胞和肝星状细胞。目前，弗朗西斯博士持有 一项 BLRD VA 优异奖（重新提交并评分，2019 年 6 月）和两项 NIH NIDDK R01 奖（角色：两者的 PI）。她 担任 NIH NIDDK 肝胆病理生理学研究组永久成员（2018-2023） 也是《Hepatology》、《Laboratory Investigation》和《PLoSOne》的编辑委员会成员。弗朗西斯博士一直是 自 2011 年起担任积极导师，并继续在研究生委员会任职，培养博士后研究员 并与临床合作伙伴发展合作。此外，自 2012 年以来，弗朗西斯博士一直保持着多项 与 VA 资助的研究人员的合作已产生大量出版物。 影响：原发性硬化性胆管炎 (PSC) 是一种长期进行性的肝脏和胆囊疾病 其特征是胆管炎症和疤痕，通常允许胆汁从胆管中排出 胆囊。患有 PSC 的患者可能没有症状或患有多种症状，例如 黄疸、瘙痒和腹痛。此外，大多数 PSC 患者（75% 以上）还患有 溃疡性结肠炎等炎症性肠病，从而使治疗策略变得复杂。的风险 PSC 包括 CCA 发病率增加，但也发现结直肠癌和胆囊癌 患有 PSC 的患者多于没有 PSC 的患者。 PSC 的病因尚不完全清楚；然而，一些研究指出 遗传联系、免疫系统故障和肠道微生物群失调。治疗方案 PSC 患者的治疗受到严重限制。有一个亚群的患者从治疗中得到缓解 胆汁酸、熊去氧胆酸盐；然而，并非所有患者都有反应。肝移植仍然是最主要的 PSC 的明确“治愈”或治疗，但移植后有复发的机会。估计的 诊断后的生存时间约为 20 年，具体取决于发现和治疗的阶段。 我们的工作表明，患者体内的组胺（主要来自肥大细胞）水平升高 PSC 患者和 CCA 患者。此外，我们还发现这些患者的肥大细胞数量增加 并且被发现靠近胆管，因此这项工作在临床上非常重要。该提案旨在确定 生物标志物和潜在的新疗法既可以缓解症状，又可以提供治疗进展，而无需任何治疗 移植。此外，由于 PSC 可以发展为 CCA（在美国的一个亚人群中增加） 退伍军人），我们还将致力于了解 PSC 的转变以及调节这种转变的信号机制 CCA 的发展。