# Valine as a Metabolic Modulator of Hematopoiesis

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $364,352

## Abstract

PROJECT SUMMARY/ABSTRACT
Hematopoietic stem cells (HSCs) are arguably the best-studied adult stem cell population and are also used in
the clinic in a form of bone marrow (BM) transplantation. Despite extensive efforts, the mechanism of how the
BM maintains HSCs and blood homeostasis remains elusive. My laboratory has begun to explore amino acids
as metabolic modulators of hematopoiesis and recently found that HSCs are highly dependent on valine.
Additionally, we have found that the BM maintains high concentrations of amino acids, approximately 50-fold
higher than in the peripheral blood. A valine-restricted diet can even replace irradiation to condition mice for HSC
transplantation, providing important proof-of-concept for the use of dietary approaches for BM conditioning.
Combined, these results led us to propose that amino acids, and in particular valine, are key components of the
BM HSC microenvironment. However, several key issues remain unresolved, including how valine modulates
HSC function and how amino acid concentrations are regulated within the BM. By answering these basic
biological questions, we aim to improve ex vivo HSC expansion and BM transplantation protocols.
In this research plan, we will: (1) define the contribution of valine catabolism to HSC function; (2) dissect the
requirements of valine catabolism and amino acid uptake in the BM microenvironment; and (3) improve BM
transplantation conditioning and outcome by modulating amino acid metabolism. In Aim 1, we will build on new
evidence that valine catabolism regulates HSC self-renewal. While this finding helps to understand why HSCs
require valine, the mechanistic relationship between HSC self-renewal and the valine catabolism pathway is not
clear. To address this, we will combine metabolic approaches with in vitro and in vivo rescue assays, to define
which valine catabolite(s) have “self-renewal promoting” activity. After identifying these biologically active
metabolites, we will be able to further investigate the mechanism of action and may even be able to improve ex
vivo HSC expansion. Aim 2 will build on this with genetic approaches to understand the importance of valine
catabolism in normal BM function. Additionally, we will test the hypothesis that BM trans-endothelial amino acid
transport is responsible for maintaining high BM amino acid concentrations and sustaining hematopoiesis. In
Aim 3, we will apply our understanding of HSC/BM amino acid regulation to optimize our proof-of-concept dietary
BM conditioning protocols. Within the hematopoietic system, T cells and B cells are also highly dependent on
valine. As these lymphoid cells are responsible for graft rejection, we will endeavor to utilize their sensitivity to
valine deprivation to extend our dietary conditioning approach to allogeneic HSC transplantation. By better
understanding the valine sensitivity of lymphoid subpopulations, we may even be able to develop methods to
“wipe” harmful immunological memory, such...

## Key facts

- **NIH application ID:** 10174920
- **Project number:** 5R01DK116944-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Hiromitsu Nakauchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $364,352
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174920

## Citation

> US National Institutes of Health, RePORTER application 10174920, Valine as a Metabolic Modulator of Hematopoiesis (5R01DK116944-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10174920. Licensed CC0.

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