A Novel Cell Death Pathway Induced by Galectin-1

描述(由申请者提供)：细胞死亡是一种关键的调控因素 发育过程、动态平衡过程和疾病过程。许多细胞死亡 已经确定了触发因素，尽管对许多 导致细胞死亡的分子途径。Galectin-1，一个家族的成员 在进化上古老的凝集素，导致胸腺细胞和T细胞的死亡。在……里面 在哺乳动物中，Galectin-1在淋巴组织、炎症部位、 在某些类型的癌症中。Galectin-1也被证明是 自身免疫性疾病的几种动物模型中的免疫抑制。Galectin-1 也可以诱导转化的上皮细胞死亡，从而使Galectin-1 介导的细胞死亡可能是调节细胞存活的基本机制 在许多组织中。其他半乳糖凝集素家族成员具有促或抗细胞凋亡作用 在不同组织中的活性，表明不同的Galectins可能 合作调控细胞死亡。此应用程序的目标是 了解Galectin-1细胞死亡的分子机制 Galectin-1与细胞表面糖蛋白受体的相互作用 以及调节细胞死亡的下游事件。 具体目标是： 1.确定半乳糖凝集素-L T细胞表面受体的特征 来传递死亡信号。CD7和CD43是糖蛋白受体 Galectin-1。多糖和多肽的特性 发送死亡信号将被识别。 2.研究半乳糖凝集素-L与T细胞结合的分子机制 相互作用来传递死亡信号。Galectin-1结合导致 T细胞表面受体重组的独特模式。我们会 确定这种相互作用所需的受体的特征，以及 研究细胞死亡是否需要受体重组。效应 Galectin-1在细胞骨架连接蛋白和肌动蛋白细胞骨架上的表达 将被描述为。检查支配T细胞的细胞与细胞的相互作用 Galectin-1介导的T细胞与T细胞结合过程中的死亡、受体重组 将对胸腺基质细胞进行检查。 3.鉴定调节Galectin-L细胞的胞内成分 死亡之路。 我们将研究蛋白激酶C和蛋白磷酸酶的作用 调节Galectin1细胞死亡的酶家族。我们决定如何 Galectin-3的表达调节T细胞对Galectin-1的敏感性。

DESCRIPTION (provided by applicant): Cell death is a critical regulatory process in development, in homeostasis, and in disease. Many cell death triggers have been identified, although little is known about many of the molecular pathways that lead to cell death. Galectin-1, a member of a family of evolutionarily ancient lectins, induces death of thymocytes and T-cells. In mammals, galectin-1 is expressed in lymphoid tissues, at sites of inflammation, and in some types of cancer. Galectin-1 has also been shown to be immunosuppressive in several animal models of autoimmune disease. Galectin-1 induces cell death of transformed epithelial cells as well, so that galectin-1 mediated cell death may be a fundamental mechanism that regulates cell survival in many tissues. Other galectin family members have pro- or anti-apoptotic activities in different tissues, suggesting that different galectins may cooperate to regulate cell death. The goal of this application is to characterize the molecular mechanism of galectin-1 cell death, to understand the interaction of galectin-1 with glycoprotein receptors on the cell surface, and the downstream events that regulate cell death. The Specific Aims are: 1. To define features of the T-cell surface receptors for galectin-l required to transmit the death signal. CD7 and CD43 are glycoprotein receptors for galectin-1. Features of the glycans and the polypeptides that are essential for sending the death signal will be identified. 2. To examine how galectin-l binding to T-cells results in molecular interactions to deliver the death signal. Galectin-1 binding results in a unique pattern of receptor reorganization on the T-cell surface. We will identify features of the receptors required for this interaction, and investigate whether receptor reorganization is required for cell death. Effects of galectin-1 on cytoskeletal linker proteins and on the actin cytoskeleton will be characterized. To examine cell-cell interactions that govern T-cell death, receptor reorganization during galectin-1 mediated binding of T-cells to thymic stromal cells will be examined. 3. To characterize intracellular components that regulate the galectin-l cell death pathway. We will examine the roles of the protein kinase C and protein phosphatase families of enzymes in regulating galectin1 cell death. We determine how galectin-3 expression regulates T-cell susceptibility to galectin-1.