# Progenitor Cells for High Endothelium in the Immune Response

> **NIH NIH R01** · PALO ALTO VETERANS INSTIT FOR RESEARCH · 2023 · $638,104

## Abstract

PROJECT SUMMARY
SUMMARY: High endothelial venules (HEV) are specialized portals for lymphocyte entry into lymphoid tissues
and sites of chronic inflammation from the blood. Along with flat walled postcapillary venules, they regulate
immune cell trafficking in physiologic and pathologic settings including autoimmune diseases, inflammation and
cancer. HEV in lymph nodes draining sites of immune challenge expand dramatically to support enhanced
lymphocyte recruitment, with new high endothelial cells (HEC) arising by proliferation and by neogenesis from
capillary resident progenitors (CRP). The molecular pathways that control HEV expansion and differentiation
from capillary precursors are as yet unclear; but generation of a comprehensive atlas of lymph node blood
endothelial cell subsets, molecular phenotypes and responses to immune challenge now allows us to identify
candidate pathways involved. Our fundamental focus in this renewal application is therefore to identify and
characterize novel mechanisms of HEV specialization and generation in the immune response. In this context
we will mechanistically define pathways that i) regulate progenitor cell homeostasis and transitional EC
expansion in immune angiogenesis; ii) induce the unique "high" endothelial morphology and metabolism of
HEV, regulating "HEVness" and function; and iii) control the cell-fate decision that directs transitional EC
towards lymphocyte-recruiting HEV (vs non-HEV PCV) differentiation. We will apply innovative approaches to
address these fundamental gaps in knowledge including scRNAseq and mass proteomic EC profiling, novel
pan-EC and CRP-specific gene-targeted mice, and nanoparticle methods to manipulate EC-subset specific
gene expression. Elucidation of the mechanisms of endothelial cell specialization and homeostasis in lymphoid
tissues, including mechanisms regulating endothelial cells that control lymphocyte homing, will lead to novel
targets and approaches for the control of autoimmune inflammation and for therapeutic regulation of immune
cell traffic for vaccination and cancer immunity.

## Key facts

- **NIH application ID:** 10592196
- **Project number:** 2R01AI130471-06
- **Recipient organization:** PALO ALTO VETERANS INSTIT FOR RESEARCH
- **Principal Investigator:** EUGENE C BUTCHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $638,104
- **Award type:** 2
- **Project period:** 2017-09-25 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592196

## Citation

> US National Institutes of Health, RePORTER application 10592196, Progenitor Cells for High Endothelium in the Immune Response (2R01AI130471-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10592196. Licensed CC0.

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