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）奖并支持博士。 希瑟·弗朗西斯（Heather Francis）的VA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州肝脏中心的科学主任 印第安纳波利斯的Richard L. Roudebush VA医疗中心的研究（ICLR）以及一位完整的教授 印第安纳州胃肠病学和肝病学部内科医学系 大学。弗朗西斯博士最近在2019年1月担任该职位，并继续她的VA资助工作 印第安纳波利斯。在搬到印第安纳州之前，弗朗西斯博士曾是德克萨斯州中部资深人士健康的研究生物学家 德克萨斯州坦普尔市的护理系统，自2012年以来，她一直在VA成立以来一直持续的VA资金 她在2016年过渡为VA BEARIT奖的职业发展奖。弗朗西斯博士的区域 兴趣和专业知识在于胆管细胞（胆管细胞）生物学和弗朗西斯博士的病理生理学 受世界知名专家Gianfranco Alpini博士（2007 - 2015年）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 与居民肝细胞相互作用，包括胆管细胞和肝脏星状细胞。目前，弗朗西斯博士持有 Blrd VA功绩（2019年6月重新提交和得分）和两个NIH NIDDK R01奖项（角色：两者的PI）。她 作为NIH NIDDK肝病病理生理研究部分的常任成员（2018- 2023） 并在肝病学，实验室调查和PLOSONE的编辑委员会上。弗朗西斯博士一直是 自2011年以来积极的心理，并继续在研究生委员会任职，培训博士后研究员 并与临床合作伙伴建立合作。此外，自2012年以来，弗朗西斯博士维持了一个数字 与VA资助的调查人员合作，导致了许多出版物。 影响：原发性硬化胆管炎（PSC）是肝脏和胆囊的长期进行性疾病 胆管的炎症和疤痕，通常使胆汁从 胆囊。患有PSC的患者可能渐近或患有无数症状，例如 珍妮丝（Janice），瘙痒和腹痛。此外，大多数PSC患者（超过75％）也患有 炎性肠疾病等溃疡性结肠炎，从而使其治疗策略变得复杂。风险 PSC包括增加CCA的发动机，但也发现了结直肠癌和胆囊癌 随后没有PSC的患者。 PSC的原因尚不清楚。但是，一些研究指出 遗传联系，免疫系统故障和肠道菌群失调。治疗选择 PSC患者受到严重限制。患者有一个子人群 胆汁酸，ursedoxyoxychaly；但是，并非所有患者都反应。肝移植仍然是最多的 对PSC的确定性“治愈”或治疗，但是移植后有可能复发。估计 诊断的生存时间约为20年，具体取决于整个发现和管理的阶段。 我们的工作表明，患者的组胺（源自肥大细胞的原发性）水平有所提高 PSC和CCA患者。此外，我们已经表明这些患者的肥大细胞数量增加 并发现接近胆管，从而使这项工作在临床上非常重要。该建议旨在确定 生物标志物和潜在的新型疗法可以减轻症状并提供治疗性进展 移植。此外，由于PSC可以发展为CCA（在美国的亚种群中增加了 退伍军人），我们还将旨在了解PSC和信号传导机制的过渡 CCA的开发。