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: 6490771
• 负责人: KATHLEEN Marie MCCORMICK
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 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 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6490771
• 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（申请人的逐字描述）：胰岛素样生长 因子 2/甘露糖 6-磷酸 (IGF2/M6P) 受体是一种多功能蛋白 具有不同配体的独特结合位点，包括 IGF2、M6P、 尿激酶型纤溶酶原激活剂受体和视黄酸。 IGF2/M6P 受体显然对于调节心脏细胞数量至关重要 胚胎发生。 IGF2/M6P 受体缺失的胚胎在出生前死亡 增生（细胞数量增加）的心脏。尚不清楚的是如何 受体调节心肌细胞数量。 受体无效增生似乎并不是由于过度增殖所致 活动;这意味着 IGF2/M6P 受体缺失的细胞死亡不正常 心。因此，我们假设 IGF2/M6P 受体调节细胞数量 通过调节影响心脏的细胞外生长因子的水平 细胞的存活和死亡。拟议的工作将侧重于确定是否 已知与 IGF2/M6P 受体相互作用的两种生长因子 IGF2 和 转化生长因子β (TGFbeta)，对于生长发育非常重要 受体缺失小鼠的心脏增生。这将在 一系列的实验。首先，我们将结合使用生化和 显微技术彻底比较细胞死亡的发生率 受体无效的心脏和对照心脏。其次，我们要认真分析 缺乏 IGF2 受体和配体的小鼠的心脏生长以确定是否 IGF2/M6P 受体以不依赖 IGF2 的方式调节心脏生长。 第三，我们将检查 TGFbeta 的表达和/或激活是否 IGF2/M6P 受体缺失胚胎中发生改变。最后，我们将尝试拯救 通过增加 IGF2/M6P 受体缺失胚胎的心脏表型 活性 TGFbeta 的内源水平。 所提出的实验将提供对分子基础的深入了解 胚胎发生过程中心肌生长的调节。异常生长是 与多种先天性心脏病以及向先天性心脏病的转变有关 成人充血性心力衰竭。更好地了解心肌如何 生长受到调节可能最终导致预防的临床方法 这两个健康问题。