The role of CD4 in macrophage differentiation and function

CD4在巨噬细胞分化和功能中的作用

• 批准号: 8490281
• 负责人: SCOTT G KITCHEN
• 金额: $ 35.47万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490281
• 关键词: Acquired Immunodeficiency Syndrome; Address; Antigen-Presenting Cells; CD4 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Canis familiaris; Cell physiology; Cells; Cessation of life; Coupled; Cytokine Gene; Defect; Derivation procedure; Development; Disease; Disease Progression; Family suidae; HIV; Helper-Inducer T-Lymphocyte; Hematopoietic; Human; Immune; Immune response; Immune system; Individual; Infection; Knowledge; Ligation; Light; Malignant Neoplasms; Microglia; Mus; Natural Killer Cells; Nature; Opportunistic Infections; Organ; Pathogenesis; Play; Primates; Process; Public Health; Research; Role; System; T cell response; T-Lymphocyte; Therapeutic; Tissues; Virus; Virus Diseases; base; cell type; cellular development; cytokine; design; embryonic stem cell; genetic manipulation; human embryonic stem cell; immune function; interest; macrophage; monocyte; novel; pathogen; protein expression; receptor; self-renewal; thymocyte; virus pathogenesis

Project Summary. The CD4 molecule has an important role in the human immune system and in the pathogenesis of HIV. A key factor in HIV pathogenesis is the use of the CD4 molecule as the primary receptor for cellular infection. In addition to CD4+ T helper cells, there are numerous other cells of the immune system that express CD4 that are susceptible to infection by HIV. One of the primary targets and an important and poorly understood reservoir for HIV in an infected individual are monocytes/ macrophages. Other than allowing HIV infection of these cells, the role of the CD4 receptor in the function and development of monocyte/macrophages is not known. We have recently determined that ligation of CD4 on monocytes/ macrophages modulates gene and cytokine protein expression as well as T cell responses. We are interested in examining this and other roles and functions of the CD4 molecule on the monocyte/ macrophage cell subset. Our central hypothesis in this proposal is that CD4 has a role in monocyte/ macrophage differentiation and function by modulating the expression of factors that control cellular development and other immune responses. This, in turn, has important implications in HIV infection and the understanding of the monocyte/ macrophage reservoir of infected cells in disease progression. This proposal will focus on addressing these issues and will focus on the following three Specific Aims: 1. To determine the mechanisms regulating CD4 expression during monocyte/ macrophage development. 2. To determine the function(s) and consequence(s) of CD4 expression during monocyte/ macrophage lineage differentiation and development. 3. To determine the role(s) of the CD4 molecule on mature monocyte/ macrophage function. To achieve this, we will utilize a novel embryonic stem cell-based system that we can genetically manipulate and examine monocyte/ macrophage differentiation and function from a cell type that is among the earliest in human hematopoietic development. In summary, it is anticipated that these studies will shed light on the potential roles and importance of CD4 in monocyte/macrophage development and/or function. Further, it is anticipated that the proposed studies will allow a more comprehensive understanding of the consequences of HIV infection in this cell type.

项目摘要。 CD4分子在人类免疫系统和HIV的发病机制中起着重要作用。 HIV发病机制中的一个关键因素是使用CD4分子作为细胞感染的主要受体。 除了CD4+T辅助细胞外，免疫系统中还有许多其他细胞表达CD4 容易感染艾滋病毒。主要目标之一和一个重要但鲜为人知的 感染者体内艾滋病毒的贮存库是单核/巨噬细胞。除了允许艾滋病毒感染 在这些细胞中，CD4受体在单核/巨噬细胞的功能和发育中的作用并不是 为人所知。 我们最近已经确定，单核/巨噬细胞上的CD4连接对基因和 细胞因子蛋白表达和T细胞反应。我们有兴趣研究这个角色和其他角色，并 CD4分子在单核/巨噬细胞亚群中的功能。我们在这方面的中心假设 有一种观点认为，在单核/巨噬细胞分化和功能过程中，CD4通过调节 表达控制细胞发育和其他免疫反应的因子。这反过来又产生了 HIV感染的重要意义及对人类免疫缺陷病毒单核/巨噬细胞库的认识 疾病进展中的受感染细胞。这项提案将重点解决这些问题，并将重点放在 以下是三个具体目标： 1.探讨单核/巨噬细胞发育过程中CD4表达的调控机制。 2.确定CD_4在单核/巨噬细胞谱系中的作用(S)及其后果(S) 差异化发展。 3.探讨CD_4分子对成熟单核/巨噬细胞功能的影响(S)。 为了实现这一点，我们将利用一种新的基于胚胎干细胞的系统，我们可以在基因上操纵它。 并从一种最早的细胞类型中检测单核/巨噬细胞的分化和功能 人类的造血发育。总而言之，预计这些研究将揭示 CD4在单核/巨噬细胞发育和/或功能中的潜在作用和重要性。更进一步说，它是 预期拟议的研究将使人们能够更全面地了解 这种细胞中的艾滋病毒感染。