BLR&D Research Career Scientist Award

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·弗朗西斯的退伍军人事务部研究项目。 候选人：希瑟·弗朗西斯博士是印第安纳州首届肝脏中心的科学主任 在印第安纳波利斯理查德·L·鲁德布什退伍军人医学中心的研究(ICLR)，以及 印第安纳大学消化和肝病分部内科医学 大学。弗朗西斯博士最近于2019年1月就任这一职位，并继续她由退伍军人事务部资助的工作 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 在德克萨斯州坦普尔的护理系统，她自2012年以来一直获得退伍军人管理局的资助，开始 职业发展奖，她在2016年转变为BLRD VA功勋奖。弗朗西斯博士的脑区 对胆管细胞(胆管细胞)生物学的病理生理学感兴趣和专业知识，弗朗西斯博士 由世界知名专家Gianfranco Alpini博士(2007-2015年)培训和指导。弗朗西斯博士有 成为肝脏肥大细胞及其对肝脏疾病的贡献以及肥大细胞如何 与驻留的肝细胞相互作用，包括胆管细胞和肝星状细胞。目前，弗朗西斯博士持有 一个BLRD VA荣誉奖(重新提交并得分，2019年6月)和两个NIH NIDDK R01奖(角色：两个都是PI)。她 担任NIH NIDDK肝胆病理生理学研究组常任成员(2018-2023年) 同时也是《肝病、实验室调查和公共科学》杂志的编辑委员会成员。弗朗西斯博士一直是一个 自2011年起积极担任导师，并继续担任研究生委员会成员，培训博士后研究员 并与临床合作伙伴开展合作。此外，自2012年以来，弗朗西斯博士一直保持着 与退伍军人管理局资助的调查人员的合作产生了许多出版物。 影响：原发性硬化性胆管炎(PSC)是一种长期进行性的肝胆疾病 以胆管发炎和结疤为特征的，这通常会使胆汁从胆管中流出 胆囊炎。患有PSC的患者可能没有症状或有各种各样的症状，如 黄疸、瘙痒和腹痛。此外，大多数PSC患者(75%以上)还患有 炎症性肠病，如溃疡性结肠炎，从而使他们的治疗策略复杂化。存在以下风险： PSC包括CCA发病率的增加，但结直肠癌和胆囊癌在 有PSC的患者多于无PSC的患者。PSC的原因尚不完全清楚；然而，一些研究指出 遗传联系、免疫系统故障和肠道微生物区系失调。治疗方案的选择 患有PSC的患者受到严重限制。有一小部分患者从治疗中得到缓解 胆汁酸，熊去氧胆酸；然而，不是所有的患者都有反应。肝移植仍然是最大的 PSC的最终“治愈”或治疗，但移植后有复发的机会。估计 根据整个发现和治疗阶段的不同，从诊断到生存时间约为20年。 我们的研究表明，患者体内组胺(主要来源于肥大细胞)水平升高。 PSC和CCA患者。此外，我们还发现这些患者的肥大细胞数量增加。 并被发现靠近胆管，因此这项工作具有非常重要的临床意义。这项提案旨在确定 生物标志物和潜在的新疗法，既能缓解症状，又能在没有 移植。此外，由于PSC可以发展为CCA(在美国的一个子人口中增加) 退伍军人)，我们还将致力于了解PSC的转变以及调节这一转变的信号机制 CCA的发展。

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.