POR In Inherited Metabolic Liver Diseases

遗传性代谢性肝病中的 POR

• 批准号: 7057343
• 负责人: PRAMOD K MISTRY
• 金额: $ 14.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057343
• 关键词: Gaucher' s disease; biological signal transduction; blood chemistry; bone morphogenetic proteins; clinical research; family genetics; gene expression; gene mutation; genetic polymorphism; genetic screening; growth factor receptors; hepatolenticular degeneration; human genetic material tag; human subject; interleukin 10; interleukin 6; macrophage; migration inhibition factor; patient oriented research; protein kinase; pulmonary hypertension; transforming growth factors

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.

描述（由申请人提供）： 该中期研究者研究人员奖的目标是扩大耶鲁大学医学院的遗传代谢肝病（IMLD）（IMLD）的研究和培训，使用Gaucher病（GD）和威尔逊病作为指数疾病。候选人Pramod K. Mistry，MB BS，博士，医学副教授，是一位受人尊敬的临床研究者，在GD中拥有独特的培训和研究经验。该提案将使Mistry博士能够扩大他当前的研究工作，并制定一项指导计划，该计划重点介绍耶鲁大学肝脏中心的IMLD，以整合临床，实验室，遗传和流行病学方法。 拟议的研究项目是Mistry博士正在进行的POR的延续。具体目的是：1。探索N370S纯合患者GD巨噬细胞反应性遗传变异对疾病严重程度变异的贡献。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功能多态性的关联：巨噬细胞迁移抑制因子（MIF），IL 6，IL 10，TNFα和TGF beta。 2。评估两个进一步的候选改性基因对1型GD/重度肺动脉高压的特定表型的贡献。因此，将检查患有严重pH的1型GD患者在TGF-β信号通路的组件中的突变：BMPRII（骨形态发生蛋白受体II）和ALK1（激活素受体样激酶1）。 指导计划的目标是在学员中发展奖学金和技术技能，以在IMLD中进行有罪分子。该培训计划包括核心课程，这是一种临床和转化研究方法中的个性化教学成分以及POR的深入监督研究项目。该培训计划得到肝T32 DK 07356的支持。