Regulation of prostate organogenesis by tissue-resident macrophages

组织驻留巨噬细胞对前列腺器官发生的调节

• 批准号: 10555589
• 负责人: Maho Shibata
• 金额: $ 35.53万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555589
• 关键词: Adoptive Transfer; Adult; Affect; Androgen Receptor; Androgens; Benign; Benign Prostatic Hypertrophy; Birth; Bone Marrow; Cell physiology; Cells; Data; Dependence; Development; Discipline; Disease; Embryo; Epithelial Cells; Fetal Liver; Foundations; Generations; Genes; Genetic; Goals; Growth; Heterogeneity; Histologic; Human; Image; Immune; Immune System Diseases; Immune Targeting; Immune system; Immunofluorescence Immunologic; Immunosuppression; Investigation; Knowledge; Lung; Macrophage; Mammary gland; Mission; Morphogenesis; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nuclear; Organ; Organogenesis; Organoids; Population; Population Heterogeneity; Property; Prostate; Prostatic Diseases; Proteins; Puberty; Public Health; Publishing; Regulation; Reporter; Research; Resolution; Role; Scientific Advances and Accomplishments; Signal Transduction; Specificity; Testing; Testis; Therapeutic; Three-Dimensional Imaging; Tissues; Urologic Diseases; Yolk Sac; cell type; diphtheria toxin fragment A; effective therapy; fetal; hormone regulation; immunoregulation; improved; in vivo; innovation; innovative technologies; insight; men; monocyte; mouse model; novel; novel strategies; receptor expression; receptor function; reproductive; research study; response; single-cell RNA sequencing; treatment strategy; tumor-immune system interactions

Project Summary/Abstract Prostate organogenesis starts prior to birth, with extensive tissue growth occurring during puberty in response to androgens after the immune system is fully functional. Androgens are generally considered immune- suppressive, so this suggests contradictory roles for immune cells in the prostate, where an immune suppressive microenvironment is needed as new prostate-specific proteins are generated, yet immune cell functions are required to promote morphogenesis and tissue growth during puberty. Our recent single-cell RNA sequencing analyses of normal mouse and human prostates revealed previously unknown heterogeneity in prostate epithelial cell types. These studies form the foundation for a new direction in which I propose to shift my focus from prostate epithelial cells to investigate the function, developmental origins, and androgen-dependence of immune cells in the prostate. The long-term goal of this research is to investigate immune cell regulation of prostate organogenesis so that we can better understand the underpinnings of benign prostate disease. This application specifically seeks to elucidate the function of macrophages during prostate organogenesis and their potential contribution to BPH progression. Our central hypothesis is that heterogeneous populations of prostate macrophages with distinct cellular origins and tissue-specific properties regulate the organogenesis and function of the prostate, and their dysregulation contributes to BPH. To test our hypothesis, Specific Aim 1 will identify the function and heterogeneity of macrophages in the developing prostate. Specific Aim 2 will determine the cellular origins of macrophages in the developing prostate and in BPH. Specific Aim 3 will identify the androgen signaling requirements of macrophage populations in the developing prostate and in BPH. Under Aim 1, we will conduct immunofluorescence analysis of macrophages in prostate tissues, incorporating high-resolution 3D imaging, live imaging, and data from single-cell RNA sequencing. For Aim 2, we will conduct genetic-lineage tracing studies of macrophages of yolk sac, fetal liver, and bone marrow origin. For Aim 3, we will test the role of AR in prostate macrophages by deleting AR in macrophages during prostate organogenesis and in a mouse model of BPH. This proposal is innovative due to the novel investigation into how immune cells contribute to promoting prostate organogenesis both prior to and during puberty in this androgen-regulated organ; the novel investigation into how AR functions in prostate immune cells to regulate organ morphogenesis and immune suppression during puberty; and the use of innovative technology. The proposed research is significant because successful completion of this proposal will elucidate the in vivo function of macrophages during prostate organogenesis; demonstrate the cellular origin of prostate macrophages across the various stages of prostate organogenesis; and clarify the in vivo role of cell-autonomous AR in macrophages during prostate organogenesis. Importantly, this project will further investigate the role of macrophages in the development of BPH, which has the potential to inform the development of improved treatment strategies for BPH.

项目概要/摘要 前列腺器官发生在出生前开始，并在青春期发生广泛的组织生长作为反应 免疫系统完全发挥作用后，会产生雄激素。雄激素通常被认为具有免疫作用 抑制性，因此这表明前列腺中免疫细胞的作用相互矛盾，其中免疫抑制 随着新的前列腺特异性蛋白的产生，需要微环境，但免疫细胞功能却受到影响。 促进青春期形态发生和组织生长所需的。我们最近的单细胞 RNA 测序 对正常小鼠和人类前列腺的分析揭示了前列腺中以前未知的异质性 上皮细胞类型。这些研究为我建议转移注意力的新方向奠定了基础 从前列腺上皮细胞中研究前列腺上皮细胞的功能、发育起源和雄激素依赖性 前列腺中的免疫细胞。这项研究的长期目标是研究免疫细胞对 前列腺器官发生，使我们能够更好地了解良性前列腺疾病的基础。这 该申请特别旨在阐明巨噬细胞在前列腺器官发生过程中的功能及其 对 BPH 进展的潜在贡献。我们的中心假设是前列腺的异质群体 具有不同细胞起源和组织特异性的巨噬细胞调节器官发生和功能 前列腺的功能失调，其失调会导致 BPH。为了检验我们的假设，具体目标 1 将确定 发育中的前列腺中巨噬细胞的功能和异质性。具体目标 2 将确定 发育中的前列腺和良性前列腺增生中巨噬细胞的细胞起源。具体目标 3 将识别雄激素 发育中的前列腺和良性前列腺增生中巨噬细胞群的信号传导需求。在目标 1 下，我们将 对前列腺组织中的巨噬细胞进行免疫荧光分析，结合高分辨率 3D 成像、实时成像和单细胞 RNA 测序数据。对于目标2，我们将进行遗传谱系 卵黄囊、胎儿肝脏和骨髓来源的巨噬细胞的追踪研究。对于目标 3，我们将测试角色 通过在前列腺器官发生期间和小鼠中删除巨噬细胞中的 AR 来减少前列腺巨噬细胞中的 AR BPH 模型。由于对免疫细胞如何发挥作用的新研究，该提议具有创新性 在青春期前和青春期期间促进前列腺这个雄激素调节器官的器官发生；小说 研究AR如何在前列腺免疫细胞中发挥作用来调节器官形态发生和免疫 青春期的抑制；以及创新技术的使用。拟议的研究意义重大，因为 该提案的成功完成将阐明前列腺期间巨噬细胞的体内功能 器官发生；证明前列腺巨噬细胞在前列腺各个阶段的细胞起源 器官发生；并阐明细胞自主 AR 在前列腺期间巨噬细胞中的体内作用 器官发生。重要的是，该项目将进一步研究巨噬细胞在发育中的作用 BPH，有可能为改善 BPH 治疗策略的开发提供信息。