POR In Inherited Metabolic Liver Diseases

遗传性代谢性肝病中的 POR

• 批准号: 6924330
• 负责人: PRAMOD K MISTRY
• 金额: $ 14.1万
• 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/6924330
• 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）： 这项以患者为导向的研究 (POR) 中的职业生涯中期研究员奖的目标是扩大遗传性代谢性肝病 (IMLD) 的研究和培训，以戈谢病 (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，医学学士、博士，医学副教授，是一位受人尊敬的临床研究者，在 GD 方面拥有独特的培训和研究经验。该提案将使 Mistry 博士能够扩大他目前的研究工作，并在耶鲁大学肝脏中心制定一个专注于 IMLD 的指导计划，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. 探讨巨噬细胞反应性的遗传变异对 N370S 纯合子患者 GD 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在 GD 中升高的细胞因子的基因功能多态性之间的关联：巨噬细胞迁移抑制因子 (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，患有严重PH的1型GD患者将检查TGF-β信号通路成分的突变：BMPRII（骨形态发生蛋白受体II）和ALK1（激活素受体样激酶1）。 导师计划的目标是培养学员的学术能力和技术技能，以便在 IMLD 中进行有功的 POR。培训计划包括核心课程、临床和转化研究方法的个性化教学部分以及 POR 方面的集中监督研究项目。该培训计划由 Liver T32 DK 07356 支持。