Investigating nerve fiber-associated macrophages in prostate development

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The George Washington University $129,990 on August 31, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847, Project Grant F31DK145242).

The award funds investigation of nerve fiber-associated macrophages in prostate development, with particular focus on elucidating the role of macrophages in prostate growth and benign prostate hyperplasia (BPH). The funded research employs lineage tracing and genetic macrophage ablation to determine whether embryonic-origin macrophages directly refine neuronal innervation during prostate growth and to characterize the distinct tissue-specific functions of embryonic versus postnatally derived macrophages in the prostate.

The period of performance runs from August 31, 2026 through February 28, 2029. Work is performed in Washington, DC 20052.

Abstract

Macrophages are innate immune cells that assume tissue-specific functions in tissue development and disease of many organs. The prostate is one of the few organs that develops postnatally and continues to grow in adulthood. Growth and function of the prostate is dependent on innervation, and ablation of prostate innervation results in abnormal prostate growth. Benign prostate hyperplasia (BPH), characterized by increased proliferation and progressive enlargement of the prostate, is a highly prevalent disease in older men and is associated with lower urinary tract dysfunction, kidney failure, and even death. An increase in macrophages in the prostate is observed with BPH progression, however the mechanisms controlling prostate growth in BPH are unclear. This proposal aims to elucidate fundamental knowledge of the role of macrophages in prostate growth. Our previous experiments using genetic macrophage ablation suggest that macrophages are important for prostate organogenesis and influence neuronal patterning of the prostate. Tissue-resident macrophages can arise from embryonic origins or derive postnatally from the bone marrow. In other organs, the hematopoietic origin of macrophages is linked to distinct tissue-specific functions. Lineage tracing studies in the GUT, skin, and brain show that nerve-associated macrophages derive from embryonic origins. Our lineage tracing of macrophages in the prostate revealed that both embryonic and postnatal origin macrophages reside in the prostate and are maintained throughout development, suggesting heterogenous functions of prostate macrophages. Based on these results, i hypothesize that a subset of embryonic-origin macrophages in the prostate directly refine neuronal innervation during prostate growth. In aim 1, i will determine the role of nerve-associated macrophages in the prostate. My preliminary studies show that transient ablation of macrophages during development results in abnormal growth of prostate epithelial cells, resembling hyperplasia. I will further assess the effects of genetic macrophage ablation on nerve morphology and indirect effects on prostate histology to elucidate the fundamental role of macrophages in prostate growth. Using EX vivo prostate explant culture, i will interrogate macrophage engulfment of neural material through live imaging and assess the direct effects of macrophages on nerve fiber function. In aim 2, i will determine the hematopoietic origin of nerve fiber-associated macrophages in the prostate. I will perform genetic lineage tracing to study the direct influence of macrophages from each origin on prostate cells and nerve fibers in CO- culture. To distinguish the function of embryonic and bone marrow origin macrophages in the mouse prostate, i will perform bulk RNA-SEQ analysis on lineage traced macrophages. Results from the genomics analysis will then be validated by immunofluorescence in lineage traced mouse tissue and tested in BPH patient samples. This proposal will provide training opportunities in technical skills, critical analysis, and scientific communication, supporting my development as an independent researcher.