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: 7870324
• 负责人: SCOTT G KITCHEN
• 金额: $ 38.12万
• 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/7870324
• 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; public health relevance; receptor; self-renewal; thymocyte; virus pathogenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The experimental approach described in this proposal is designed to address the central hypothesis that the CD4 molecule has a broader function in the immune response, and by extension in HIV pathogenesis, than its capacity on CD4+ T helper cells. These studies will increase our knowledge of how the CD4 molecule influences monocyte/ macrophage development and immune function and how HIV may impact this process; thus, increasing our understanding of the mechanisms of HIV infection and pathogenesis. Further, the use of embryonic stem cells in these studies, due to their high plasticity, self-renewal ability, and ability to be genetically manipulated, may allow the development of immune replacement therapeutic strategies to be developed for HIV and other similar diseases.

描述（由申请人提供）：CD4分子在人免疫系统和HIV发病机理中具有重要作用。 HIV发病机理的关键因素是将CD4分子用作细胞感染的主要受体。除了CD4+ T辅助细胞外，免疫系统的其他许多细胞表达CD4容易受到HIV感染。单核细胞/巨噬细胞是受感染个体中HIV的重要目标之一，并且是重要且知之甚少的水库。除了允许艾滋病毒感染这些细胞外，CD4受体在单核细胞/巨噬细胞功能和发育中的作用尚不清楚。我们最近确定CD4在单核细胞/巨噬细胞上的连接会调节基因和细胞因子蛋白表达以及T细胞反应。我们有兴趣检查CD4分子在单核细胞/巨噬细胞子群上的此作用和其他功能。我们在该提案中的中心假设是，通过调节控制细胞发育和其他免疫反应的因素的表达，CD4在单核细胞/巨噬细胞分化和功能中起作用。反过来，这对疾病进展中感染细胞的单核细胞/巨噬细胞储量的理解具有重要意义。该提案将着重于解决这些问题，并将集中于以下三个特定目标：1。确定在单核细胞/巨噬细胞发展过程中调节CD4表达的机制。 2。确定单核细胞/巨噬细胞谱系分化和发育过程中CD4表达的功能和后果。 3。确定CD4分子在成熟单核细胞/巨噬细胞功能上的作用。为了实现这一目标，我们将利用一种新型的胚胎干细胞系统，我们可以从遗传操纵和检查单核细胞/巨噬细胞分化和功能中，该细胞类型是人类造血性发育中最早的细胞类型。总而言之，预计这些研究将阐明CD4在单核细胞/巨噬细胞发育和/或功能中的潜在作用和重要性。此外，预计拟议的研究将使人们对这种细胞类型的艾滋病毒感染的后果有更全面的了解。公共卫生相关性：本提案中描述的实验方法旨在解决中心假设，即CD4分子在免疫反应中具有更广泛的功能，而在HIV发病机理中扩展的功能比其在CD4+ T辅助细胞上的容量。这些研究将增加我们对CD4分子如何影响单核细胞/巨噬细胞发育和免疫功能以及HIV如何影响这一过程的了解。因此，增加了我们对HIV感染和发病机理机制的理解。此外，由于胚胎干细胞在这些研究中的使用，由于其高可塑性，自我更新能力和遗传操纵的能力，可能允许开发免疫替代治疗策略，以用于HIV和其他类似疾病。