A Novel Cell Death Pathway Induced by Galectin-1

描述（由申请人提供）：细胞死亡是一个关键的调节因素， 在发展过程中，在稳态中，在疾病中。许多细胞死亡 触发因素已经确定，尽管对许多 导致细胞死亡的分子途径。半乳糖凝集素-1，一个家庭的成员， 在进化上古老的凝集素，诱导胸腺细胞和T细胞的死亡。在 在哺乳动物中，半乳糖凝集素-1在淋巴组织中，在炎症部位， 和某些类型的癌症。半乳糖凝集素-1也被证明是 在几种自身免疫性疾病动物模型中的免疫抑制。半乳糖凝集素-1 也诱导转化的上皮细胞的细胞死亡，使得半乳糖凝集素-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凋亡或抗凋亡作用。 在不同组织中的活性，表明不同的半乳糖凝集素可能 共同调节细胞死亡。此应用程序的目标是 描述半乳糖凝集素-1细胞死亡的分子机制， 半乳糖凝集素-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.为了确定所需的半乳糖凝集素-l的T细胞表面受体的特征， 传送死亡信号CD 7和CD 43是糖蛋白受体， 半乳糖凝集素-1。聚糖和多肽的特征对于 发出死亡信号的人会被识别出来 2.为了检查半乳糖凝集素-I如何与T细胞结合导致分子免疫应答， 传递死亡信号半乳糖凝集素-1结合导致 T细胞表面受体重组的独特模式。我们将 识别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。影响 半乳糖凝集素-1对细胞骨架连接蛋白和肌动蛋白细胞骨架的影响 将被定性。为了研究细胞间的相互作用， 死亡，半乳糖凝集素-1介导的T细胞与 检查胸腺基质细胞。 3.为了表征调节半乳糖凝集素-l细胞的细胞内组分， 死亡之路 我们将研究蛋白激酶C和蛋白磷酸酶的作用 在调节galectin 1细胞死亡的酶家族。我们决定如何 半乳糖凝集素-3表达调节T细胞对半乳糖凝集素-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.