POR In Inherited Metabolic Liver Diseases

描述(由申请人提供)： 这一以患者为中心的研究(POR)职业中期研究人员奖的目标是扩大耶鲁医学院以高谢病(GD)和威尔逊病(Wilson)为指标的遗传性代谢性肝病(IMLD)的研究和培训。候选人普拉莫德·K·密斯特里，MBA学士，博士，医学副教授，是一位受人尊敬的临床研究员，在GD方面拥有独特的培训和研究经验。这项建议将使密斯特里博士能够扩大他目前的研究努力，并在耶鲁大学肝脏中心开发一个以IMLD为重点的指导计划，将临床、实验室、遗传学和流行病学方法结合在一起。 拟议的研究项目是密斯特里博士正在进行的POR的延续。具体目的是：1.探讨N370S纯合子患者巨噬细胞反应性基因变异对疾病严重程度的影响。该提案旨在调查疾病严重程度与编码细胞因子基因功能多态性的关系，这些细胞因子在GD中升高：巨噬细胞移动抑制因子(MIF)、IL 6、IL 10、肿瘤坏死因子α和转化生长因子β。2.评估另外两个候选修饰基因对1型GD/重度肺动脉高压的特定表型的贡献。因此，患有重度PH的1型GD患者将接受转化生长因子-β信号通路成分的突变检查：BMPRII(骨形态发生蛋白受体II)和ALK1(激活素受体样激酶1)。 导师计划的目标是发展学员的学术和技术技能，以便在国际管理硕士学位课程中进行有价值的POR。培训计划包括核心课程、临床和转化性研究方法的个性化教学部分以及POR的密集监督研究项目。本培训项目由Liver T32 DK 07356提供支持。

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.