IN VIVO EFFECTS OY Y-SECRETASE INHIBITION IN THE IMMUNE SYSTEM

伽马分泌酶催化多种底物的裂解，其中几种已知在 正常免疫系统的功能。我们的假设是LY411,575(以下简称LY411,575)对伽马分泌酶的抑制作用 LY)在体外和体内都有免疫抑制/抗炎作用。在我们的 初步数据显示，抑制γ-分泌酶对免疫功能有几个深远的影响。 特别是，我们提供的证据表明，阻断伽马分泌酶会抑制T细胞的增殖， 干扰素-γ的分泌、核因子-kB的激活、抗体的产生和初始CD4+T细胞的分化 细胞转化为Th1细胞。虽然在许多情况下我们有令人信服的数据表明伽马分泌酶 通过激活Notch信号对免疫系统的影响，伽马分泌酶的其他靶点要求 对价。在这个应用中，我们提出了四个特定的目的，旨在阐明伽马分泌酶在正常免疫系统功能中的作用，并确定其生理靶点(S 正常免疫功能中的酶。此外，因为我们有强有力的证据表明抑制 伽马分泌酶降低实验性自身免疫性脑脊髓炎(EAE)的严重程度--一项已有文献记载的研究 ，我们将把我们对正常免疫反应的研究扩展到 探讨γ-分泌酶在EAE发病和加重中的作用。我们还将探索 LY诱导调节性T细胞聚集的可能性。最后，我们有证据表明，抑制 伽马分泌酶显著抑制核因子-KB活性，这是一种在两种肿瘤中都起重要作用的蛋白质 发展和炎症一样重要。在我们的最后一个目标中，我们描述了旨在确定 γ-分泌酶调节下游核因子-kB活性的机制。这项提议的目标是 确定γ-分泌酶在正常免疫功能中所起的作用。这些研究将提供有价值的 这两个数据都告诉我们使用伽马分泌酶抑制剂作为一种潜在的治疗药物在 炎症，以及提醒我们任何不良的影响，这种抑制作用的正常免疫功能。

Gamma-secretase catalyzes the cleavage of multiple substrates, several of which are known to play a role in the function of a normal immune system. Our hypothesis is that gamma-secretase inhibition by LY411,575 (hereafter referred to as LY) will have immunosuppressive/anti-inflammatory effects both in vitro and in vivo. In our preliminary data we show that inhibition of gamma-secretase has several profound effects on immune function. In particular, we provide evidence that blockade of gamma-secretase results in inhibition of T cell proliferation, interferon-gamma (IFNgamma) secretion, NF-KB activation, antibody production, and differentiation of naive CD4+ T cells into Th1 cells. While in many instances we have convincing data suggesting that gamma-secretase exerts its effects on the immune system through the activation of Notch signaling, other targets of gamma-secretase require consideration. In this application, we present four specific aims designed both to elucidate the role of gamma-secretase in the functioning of a normal immune system and to identify the physiological target(s) of this enzyme in normal immune function. Additionally, because we have strong evidence linking inhibition of gamma-secretase to decreased severity of experimental autoimmune encephalomyelitis (EAE), a well-documented Th1-mediated disease, we will extend our studies of normal immune responses to an examination of the role of gamma-secretase in the initiation and exacerbation of EAE. We also will explore the possibility that LY induces a population of regulatory T cells. Finally, we have evidence that inhibition of gamma-secretase results in significant inhibition of NF-KB activity, a protein with prominent roles in both tumor development as well as inflammation. In our last aim, we describe experiments designed to determine the mechanisms by which gamma-secretase may regulate downstream NF-KB activity. The goal of this proposal is to establish the role played by gamma-secretase in normal immune function. These studies will provide valuable data that both inform us of the efficacy of the use of gamma-secretase inhibitors as a potential therapeutic agent in inflammation, as well alert us to any undesirable effects of this inhibitor on normal immune function.