REGULATION OF APOPTOSIS BY NOS

描述(改编自《调查者摘要》)：一氧化氮(NO) 是一种小的、高活性的气体，由一氧化氮合酶(NOS)合成。 小鼠白细胞中的一氧化氮合酶活性已被证明发挥着重要作用 在小鼠免疫反应中。然而，一氧化氮合酶在人体免疫中的作用 由于一氧化氮合酶在人类体内的相关影响，该系统仍备受争议 白细胞一直很难证明。我们的初步数据 表明一氧化氮合酶在人类中有极低水平的结构性表达 淋巴细胞或单核细胞来源的细胞系调节细胞凋亡。我们 假设一氧化氮合酶活性调节人原代细胞的细胞凋亡 淋巴细胞和/或单核细胞以及细胞系，因此， 一氧化氮合酶活性在人体免疫系统中起着生理上相关的作用。 在具体目标1中，我们将通过确定是否 人初级淋巴细胞和单核细胞中一氧化氮合酶活性的调节 自发性或Fas诱导的细胞凋亡。在特定目标2中，人类淋巴细胞 将以细胞系为模型来研究一氧化氮合酶的作用机制 抑制Fas诱导的细胞凋亡。我们的假设是一氧化氮合酶活性 从Fas相关蛋白水平抑制Fas诱导的细胞凋亡 复杂的队形。拟议的研究将对免疫学做出贡献 和一氧化氮场。这些研究将澄清一氧化氮合酶活性是否具有 在人类和小鼠免疫系统中的生理作用：意志 深入了解一氧化氮合酶活性发挥生物学作用的机制 对人类细胞的影响；并将阐明一种新的一氧化氮合酶依赖的调节 Fas诱导的细胞凋亡。最终，这些研究可能导致 以一氧化氮为基础的疗法的发展，用于治疗与 细胞凋亡的失调包括自身免疫性疾病、癌症和 获得性免疫缺陷综合症。

DESCRIPTION (Adapted from the Investigator's abstract): Nitric oxide (NO) is a small, highly reactive gas synthesized by the enzyme NO synthase (NOS). NOS activity in murine leukocytes has been shown to play an important role in the murine immune response. However, the role of NOS in the human immune system remains highly controversial because NOS-associated effects in human leukocytes have been very difficult to demonstrate. Our preliminary data indicate that very low levels of NOS expressed constitutively in human lymphocyte or monocyte-derived cells lines regulate apoptosis. We hypothesize that NOS activity regulates apoptosis in human primary lymphocytes and/or monocytes as well as in cell lines, and therefore, that NOS activity has a physiologically relevant role in the human immune system. In Specific Aim 1, we will test this hypothesis by determining if NOS-activity in human primary lymphocytes and monocytes regulates spontaneous or Fas-induce apoptosis. In Specific Aim 2, human lymphocytic cell lines will be used as models to investigate the mechanism by which NOS inhibits Fas-induced apoptosis. Our hypothesis is that NOS activity inhibits Fas-induced apoptosis at the level of Fas-associated protein complex formation. The proposed studies will contribute ot the immunology and nitric oxide fields. The studies will clarify whether NOS activity has a physiologic role in the human as well as the murine immune system: will provide insight into the mechanism by which NOS activity exerts biological effects in human cells; and will elucidate a novel NOS-dependent regulation of Fas-induced apoptosis. Ultimately these studies may lead to the development of NO-based therapies to treat disorders associated with dysregulation of apoptosis including autoimmune diseases, cancer and the acquired immunodeficiency syndrome.