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.

项目摘要/摘要 前列腺器官发生在出生前就开始了，在青春期有广泛的组织生长。 在免疫系统完全发挥作用后对雄激素产生影响。雄激素通常被认为是免疫的- 抑制性，所以这表明免疫细胞在前列腺中扮演着相互矛盾的角色，在前列腺中，免疫抑制 随着新的前列腺特异性蛋白的产生，需要微环境，但免疫细胞的功能 在青春期促进形态发生和组织生长所必需的。我们最新的单细胞RNA测序 对正常小鼠和人类前列腺的分析揭示了以前未知的前列腺的异质性 上皮细胞类型。这些研究为我提议转移重点的新方向奠定了基础 从前列腺上皮细胞中研究雄激素的功能、发育来源和雄激素依赖性 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调节 这样我们才能更好地了解良性前列腺疾病的基础。这 应用特异地试图阐明巨噬细胞在前列腺器官发生过程中的功能及其 对良性前列腺增生症进展的潜在贡献。我们的中心假设是不同种类的前列腺癌 巨噬细胞具有不同的细胞来源和组织特异性，调节器官的发生和功能 而它们的失调导致了BPH。为了检验我们的假设，特定目标1将确定 巨噬细胞在前列腺发育中的功能和异质性。具体目标2将决定 巨噬细胞在发育中的前列腺和前列腺增生症中的细胞起源。特定目标3将确定雄激素 巨噬细胞群在前列腺发育和良性前列腺增生症中的信号需求。在目标1下，我们将 结合高分辨率3D，对前列腺组织中的巨噬细胞进行免疫荧光分析 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、胎肝和骨髓来源的巨噬细胞示踪研究。对于目标3，我们将测试角色 在前列腺器官发生和小鼠体内通过删除巨噬细胞中的AR来表达AR 良性前列腺增生症模型。这一建议是创新的，因为对免疫细胞如何在 在这个受雄激素调节的器官中促进青春期前和青春期期间的前列腺器官发生； AR在前列腺免疫细胞中调节器官形态发生和免疫功能的研究 青春期的压抑；以及创新技术的使用。这项拟议的研究具有重要意义，因为 这一提议的成功完成将阐明巨噬细胞在前列腺中的体内功能。 器官发生；证明前列腺巨噬细胞在前列腺不同阶段的细胞起源 器官发生；并阐明细胞自主AR在前列腺巨噬细胞中的体内作用 器官发生。重要的是，这个项目将进一步研究巨噬细胞在糖尿病发展中的作用。 BPH，这有可能为BPH改进治疗策略的发展提供信息。