Function of the IGF2/M6P Receptor in Heart Development

描述(申请者逐字描述)：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质 与IGF2、M6P等不同配体具有不同的结合位点， 尿激酶型纤溶酶原激活物受体和维甲酸。IGF2/M6P 受体显然是调节心脏细胞数量的关键 胚胎发生。IGF2/M6P受体缺失的胚胎在出生前死亡 心脏增生(细胞数量增加)。尚不清楚的是， 受体调节心肌细胞的数量。 受体缺失型增生似乎不是过度增殖所致 活性；这意味着IGF2/M6P受体缺失的细胞死亡是不正常的 红心。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水平 细胞的存活和死亡。拟议的工作将集中于确定 已知的与IGF2/M6P受体相互作用的两种生长因子IGF2和IGF2 转化生长因子β(TGFβ)，在血管生成中起重要作用。 受体缺失小鼠的心脏增生。这一点将在 一系列的实验。首先，我们将使用生化和生物化学的组合 用显微技术彻底比较细胞死亡发生率 受体无效并控制心脏。第二，我们将仔细分析 缺乏IGF2受体和配体的小鼠心脏生长 IGF2/M6P受体以不依赖IGF2的方式调节心脏生长。 第三，我们将研究转化生长因子β的表达和/或激活是否 在IGF2/M6P受体缺失的胚胎中发生改变。最后，我们将尝试营救 IGF2/M6P受体缺失胚胎心脏表型 内源性活性的转化生长因子β水平。 拟议中的实验将提供对 胚胎发育过程中的心肌生长调控。异常生长是 与几种先天性心脏缺陷以及过渡到 成人充血性心力衰竭。更好地了解心肌是如何 生长受到调控可能最终导致临床预防方法的出现 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.