# Regulation of Sexual Differentiation in Malaria Parasites

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $556,911

## Abstract

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PROJECT SUMMARY/ABSTRACT
Malaria is the mosquito-borne disease responsible for the greatest morbidity and mortality world-wide. After
significant reductions over the past two decades, malaria incidence and mortality have plateaued over the last
five years highlighting the need for additional interventions. Malaria transmission requires parasites to
differentiate from the replicating asexual blood stages to non-replicating male and female gametocytes
necessary to infect mosquitos. The early stages of gametocyte development are a key period during which
parasites not only need to initiate the gametocyte-specific transcriptional program, but must also block
expression of genes that lead to cell-cycle entry associated with asexual replication. Our long-term goal is to
block transmission and replication of malaria parasites by interfering with the regulatory mechanisms that
govern this essential point of control in the parasite lifecycle. Recent studies reported specific up-regulation of
chromatin-modifying enzymes in sexually committed parasites, suggesting that chromatin re-organization plays
a crucial role during the asexual to gametocyte transition. While technical barriers have thwarted studying
chromatin organization and gene expression in these critical early stages of gametocyte development, a
recently published study observed specific expansion of subtelomeric heterochromatin domains in more
mature gametocytes. This proposal aims to test the hypothesis that restructuring of the parasite chromatin
landscape in sexually committed parasites and early gametocytes is critical for the developmental switch from
asexual replication to the formation of transmissible forms. New approaches, including single-cell
transcriptomics and cell-type specific chromatin analysis, now allow researchers to define gene expression and
chromatin organization during early gametocyte development for the first time (Aim 1) and study the function of
genes critical for regulation of chromatin specifically during gametocyte development. Experiments in Aim 2
will define the critical role of putative histone demethylases in gametocyte development. While these enzymes
appear individually dispensable for asexual growth in vitro, they are notably upregulated in gametocytes, and
early gametocytes are highly susceptible to inhibitors of these enzymes, with susceptibility peaking in
gametorings and Stage I gametocytes. Lastly, Aim 3 focuses on defining the role of a newly identified DNA-
binding protein in heterochromatin mediated gene-silencing during gametocyte development. Preliminary
experiments show that loss of expression results in aberrant gametocyte development, upregulation of
heterochromatin-silenced genes, and alterations in chromatin organization. The proposed experiments will
offer a first window into the critical early stages of gametocyte development and provide new targets for
transmission blocking strategies.
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## Key facts

- **NIH application ID:** 9950997
- **Project number:** 5R01AI141965-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Bjorn Felix Caesar Kafsack
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $556,911
- **Award type:** 5
- **Project period:** 2019-06-12 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9950997

## Citation

> US National Institutes of Health, RePORTER application 9950997, Regulation of Sexual Differentiation in Malaria Parasites (5R01AI141965-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9950997. Licensed CC0.

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