POR In Inherited Metabolic Liver Diseases

描述（由申请人提供）： 这项以患者为导向的研究（POR）中期职业研究者奖的目标是扩大遗传性代谢性肝病（IMLD）的研究和培训，使用戈谢病（GD）和威尔逊病作为耶鲁大学医学院的指标疾病。候选人Pramod K. Mistry，MB BS，PhD.，医学副教授，是一位受人尊敬的临床研究者，在GD拥有独特的培训和研究经验。这项提案将使Mistry博士能够扩大他目前的研究工作，并开发一个指导计划，重点关注耶鲁肝脏中心的IMLD，整合临床，实验室，遗传学和流行病学方法。 拟议的研究项目是Mistry博士正在进行的POR的延续。具体目标是：1。探讨N370 S纯合子GD患者巨噬细胞反应性的遗传变异对疾病严重程度变化的贡献。该提案旨在研究疾病严重程度与编码GD中升高的细胞因子的基因中的功能多态性的关联：巨噬细胞移动抑制因子（MIF），IL 6，IL 10，TNF α和TGF β。2.评估另外两个候选修饰基因对1型GD/重度肺动脉高压特定表型的贡献。因此，将检查患有重度PH的1型GD患者的TGF-β信号通路组分中的突变：BMPRII（骨形态发生蛋白受体II）和ALK 1（激活素受体样激酶1）。 导师计划的目标是培养学员的奖学金和技术技能，以便在IMLD中进行有价值的POR。该培训计划由核心课程、临床和转化研究方法的个性化教学部分以及POR中的强化监督研究项目组成。该培训计划由Liver T32 DK 07356支持。

DESCRIPTION (provided by applicant): The goal of this Mid-Career Investigator Award in patient-oriented research (POR) is to expand research and training in inherited metabolic liver diseases (IMLDs), using Gaucher disease (GD) and Wilson disease as index diseases at Yale School of Medicine. The candidate Pramod K. Mistry, MB BS, PhD., an Associate Professor of Medicine, is a respected clinical investigator with unique training and research experience in GD. This proposal will enable Dr. Mistry to expand his current research efforts and to develop a mentoring program that focuses on IMLDs at Yale's Liver Center integrating clinical, laboratory, genetic and epidemiologic approaches. The proposed research project is a continuation of Dr Mistry's ongoing POR. Specific aims are: 1. To explore the contribution of genetic variation in macrophage responsiveness to variation of disease severity in GD in N370S homozygous patients. The proposal seeks to investigate association of disease severity with functional polymorphisms in genes encoding the cytokines that are elevated in GD: Macrophage migration inhibitory factor (MIF), IL 6, IL 10, TNF alpha and TGF beta. 2. To evaluate two further candidate modifier genes for their contribution to a specific phenotype of type 1 GD/severe pulmonary hypertension. Thus, type 1 GD patients with severe PH will be examined for mutations in components of TGF-beta signaling pathway: BMPRII (bone morphogenetic protein receptor II) and ALK1 (activin receptor-like kinase 1). The goals of the mentorship program are to develop scholarship and technical skills in trainees to conduct meritorious POR in IMLDs. The training program consists of a core curriculum, an individualized didactic component in methods of clinical and translational research and an intensively supervised research project in POR. This training program is supported by Liver T32 DK 07356.