Function of the IGF2/M6P Receptor in Heart Development

描述（申请人逐字描述）：胰岛素样生长 胰岛素样生长因子2/6-磷酸甘露糖（IGF 2/M6 P）受体是一种多功能蛋白 具有不同的配体结合位点，包括IGF 2，M6 P， 尿激酶型纤溶酶原激活物受体和视黄酸。IGF2/M6P 受体对于调节心脏细胞数量显然是至关重要的， 胚胎发生IGF 2/M6 P受体缺失胚胎在出生前死亡， 心脏增生（细胞数量增加）。不清楚的是， 受体调节心肌细胞数量。 受体无效性增生似乎不是由于过度增殖 活性;这意味着IGF 2/M6 P受体缺失的细胞死亡低于正常水平 心中因此，我们假设IGF 2/M6 P受体调节细胞数量， 通过调节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IGF 2/M6 P受体相互作用的两种生长因子，IGF 2和 转化生长因子β（TGF β），对于 受体缺失小鼠的心脏增生。这一点将在 一系列的实验。首先，我们将使用生物化学和 显微镜技术来彻底比较细胞死亡的发生率， 受体无效和对照心脏。第二，我们要认真分析 缺乏IGF 2受体和配体的小鼠的心脏生长，以确定 IGF 2/M6 P受体以IGF 2非依赖性方式调节心脏生长。 第三，我们将研究TGF β的表达和/或激活是否与肿瘤的发生有关。 在IGF 2/M6 P受体缺失的胚胎中改变。最后，我们将尝试拯救 通过增加IGF 2/M6 P受体缺失胚胎的心脏表型， 内源性活性TGF β水平。 拟议的实验将提供深入了解的分子基础， 胚胎发育过程中的心肌生长调节。异常增长是 与几种先天性心脏缺陷有关， 成人充血性心力衰竭更好地了解心肌 生长受到调控可能最终导致临床方法， 这两个健康问题。

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.