# Runx1 Haplodeficiency, Endocytosis and Vesicle transport

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $449,209

## Abstract

Project Summary
RUNX1 is a major hematopoietic transcription factor and RUNX1 haplodeficiency (RHD)
is characterized by familial thrombocytopenia and impaired platelet function. We have a
longstanding interest in the molecular basis of inherited platelet dysfunction, particularly
related to RHD. Numerous platelet abnormalities have been described in RHD, several
by us, and include deficiencies of dense granule (DG) and α-granules (AG). Our platelet
expression profiling studies in a patient with RHD showed that several genes are down
regulated (MYL9, PRKCQ, ALOX12, PF4, PLDN, PCTP); and we have shown that these
are direct RUNX1 transcriptional targets and impact platelet/megakaryocyte (MK)
biology. The overall objective of this proposal is to obtain new insights into the
mechanisms of endocytosis, vesicle trafficking, and α-granule formation in platelets/MK
through the study of phenotypic abnormalities and genes dysregulated in RHD. This
project builds on unique abnormalities identified by us in RHD. We have reported in our
patient that platelet albumin and IgG (incorporated by bulk endocytosis into AG) are
decreased. Our expression profiling studies show that platelet RAB1B, RAB31 and
DNM3 – three GTPases closely linked to vesicle trafficking are decreased. Little is
currently known regarding the mechanisms regulating endocytosis in platelets/MK or the
role of these GTPases. Our hypothesis is that mechanisms of endocytosis and vesicle
trafficking are impaired in RHD. Aim 1 is to obtain insights into mechanisms regulating
endocytosis in platelets/MK through the study of mechanisms leading to the decreased
platelet albumin and IgG in RHD. We will study uptake and transport of albumin and IgG
in normal and RHD platelets, study the effect of downregulation of RUNX1, RAB1B,
RAB31 and DNM3 on these processes in MK, perform studies using markers of
secretory and endocytic pathways of vesicle trafficking. Aim 2 is to understand the
mechanisms leading to AG deficiency in RHD. We will study: platelet AG in normal and
RHD platelets focusing on selected AG proteins; the effect of downregulation of RUNXI,
RAB1B, RAB31and DNM3 on AG and trafficking of AG proteins in MK. These studies
will be performed on 5-6 patients with RHD and using induced pluripotent stem cells
(IPSCs) already developed from a RHD patient. They will provide important new insights
into endocytosis and vesicle trafficking in platelets/MK, about which little is presently
known.
Relevance
Platelets play a major role in hemostasis, thrombosis, inflammation, atherosclerosis and
handling of pathogens. Our studies will provide new information on the basic aspects of
platelet/MK function through studies in human RUNX1 haplodeficiency, a unique
reservoir of information. This information will lay the foundation for new therapeutic
approaches for both thrombotic and bleeding disorders.

## Key facts

- **NIH application ID:** 9856507
- **Project number:** 5R01HL137376-03
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Angara Koneti Rao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $449,209
- **Award type:** 5
- **Project period:** 2018-02-05 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856507

## Citation

> US National Institutes of Health, RePORTER application 9856507, Runx1 Haplodeficiency, Endocytosis and Vesicle transport (5R01HL137376-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9856507. Licensed CC0.

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