# Project 2: Extracellular Glycosylation and Blood Cell Production

> **NIH NIH P01** · VERSITI BLOOD HEALTH, INC. · 2021 · $622,318

## Abstract

Project 2 – Project Summary
Maintaining hematopoiesis is critical for life. Generating the proper numbers of functional blood cells across all
lineages requires cell-intrinsic developmental programs, but these programs require guidance from cell-extrinsic
mechanisms that correctly convey the physiologic needs for these cells. Glycans on the cell surface and in the
extracellular milieu reside at the interphase through which the cell-extrinsic cues are conveyed. The overarching
Program Hypothesis is that cell-intrinsic and extrinsic glycan-mediated mechanisms regulate maintenance,
differentiation, and function of hematopoietic cells.
Glycosyltransferases such as the sialyltransferase ST6GAL1 are also residents of the extracellular milieu. Our
preliminary data point to a role for the extracellular, or extrinsic ST6GAL1, and possibly other
glycosyltransferases in the marrow to influence hematopoietic decisions on multiple levels of blood cell
development. Outside of the marrow, platelets upon activation release the sialic acid donor substrate required
to drive extrinsic sialyltransferase catalysis. Together with Project 1, we will explore the idea that
megakaryocytes, the precursors of platelets, control marrow extrinsic sialylation by a similar mechanism.
Together with Project 3, we have uncovered a totally unexpected interaction between glycosaminoglycan
components of the extracellular matrix with ST6GAL1, and we have identified a number of GAG-mimetics with
striking ability to modulate extrinsic ST6GAL1 sialylation on target cells.
Disturbed hematopoiesis with highly heterogenous presentation and varied underlying driver mutations is the
defining hallmark of clonal myeloid diseases such as myeloproliferative neoplasms (MPN) and myelodysplastic
syndromes (MDS). However, a key common feature of MPN and MDS is dysplastic megakaryocytes with altered
circulating platelet numbers and function. Our preliminary data point to distinct glycosylation signatures
associated with platelets from patients of these diseases, suggesting fundamental alterations to the bone marrow
environment and the megakaryocytes that produce the platelets. We hypothesize that glycosylation, especially
extrinsic glycosylation, regulates blood cell homeostasis, ultimately impacting the number and function of
circulating blood cells in health and in disease. We will test this hypothesis in three Specific Aims to 1) understand
how extrinsic ST6GAL1 regulates HSPC maintenance; 2) understand how extrinsic sialylation in the marrow is
regulated; and 3) initiate a first-time study on how glycosylation is modified in clinical MDS and MPN and in
mouse models. The proposed study is expected to yield transformative understanding of extrinsic glycosylation
in cell-niche interactions critical to maintaining blood cell production. This is also a pioneering investigation into
the glycoscience of clinical MDS and MPN, with potential for novel therapeutics and diagnostics.

## Key facts

- **NIH application ID:** 10088969
- **Project number:** 1P01HL151333-01A1
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** Joseph TY Lau
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $622,318
- **Award type:** 1
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10088969

## Citation

> US National Institutes of Health, RePORTER application 10088969, Project 2: Extracellular Glycosylation and Blood Cell Production (1P01HL151333-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10088969. Licensed CC0.

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