Function of the IGF2/M6P Receptor in Heart Development

IGF2/M6P 受体在心脏发育中的功能

• 批准号: 6692637
• 负责人: KATHLEEN Marie MCCORMICK
• 金额: $ 19.63万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-12 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6692637
• 关键词: cardiac myocytes; cell death; cell growth regulation; embryo /fetus; genetically modified animals; heart; histogenesis; hyperplasia; insulinlike growth factor; laboratory mouse; ligands; mammalian embryology; mannose 6 phosphate; protein protein interaction; protein structure function; receptor; receptor expression; thrombospondins; transforming growth factors

DESCRIPTION (the applicant's description verbatim): The insulin-like growth factor 2/mannose 6-phosphate (IGF2/M6P) receptor is a multi-functional protein with distinct binding sites for diverse ligands including IGF2, M6P, urokinase-type plasminogen activator receptor and retinoic acid. The IGF2/M6P receptor is clearly critical for regulating heart cell number during embryogenesis. IGF2/M6P receptor-null embryos die before birth with hyperplastic (increased cell number) hearts. What is not clear is how the receptor regulates cardiac cell number. Receptor-null hyperplasia does not appear to be due to excessive proliferative activity; this implies that cell death is subnormal in IGF2/M6P receptor-null hearts. Thus, we hypothesize that the IGF2/M6P receptor regulates cell number by modulating the levels of extracellular growth factors that affect cardiac cell survival and death. The proposed work will focus on determining whether two growth factors known to interact with the IGF2/M6P receptor, IGF2 and transforming growth factor beta (TGFbeta), are important for the development of cardiac hyperplasia in receptor-null mice. This will be critically examined in a series of experiments. First, we will use a combination of biochemical and microscopic techniques to thoroughly compare the incidence of cell death in receptor-null and control hearts. Second, we will perform a careful analysis of cardiac growth in mice that lack both IGF2 receptor and ligand to determine if the IGF2/M6P receptor regulates cardiac growth in an IGF2-independent manner. Third, we will examine whether expression and/or activation of TGFbeta are altered in IGF2/M6P receptor-null embryos. Finally, we will attempt to rescue the cardiac phenotype in IGF2/M6P receptor-null embryos by increasing endogenous levels of active TGFbeta. The proposed experiments will provide insight into the molecular basis of myocardial growth regulation during embryogenesis. Abnormal growth is associated with several congenital heart defects as well as the transition to congestive heart failure in adults. A better understanding of how myocardial growth is regulated may ultimately lead to clinical approaches for preventing both of these health problems.

描述（申请人逐字描述）：胰岛素样生长