# Signal perception and transduction regulating Giardia cyst formation

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $515,942

## Abstract

PROJECT SUMMARY/ABSTRACT
 Giardia lamblia, the causative agent of giardiasis, leads to gastrointestinal disorders, long-term growth
defects and even death. Estimates place worldwide incidence at over 200 million symptomatic cases per year.
Of concern, up to 20% of giardiasis cases are resistant to front-line clinical treatments, and resistance to all major
antigiardial drugs has been reported. In addition to their increasing lack of effectiveness, front-line and second-
line nitro drugs act intracellularly via non-specific free radical generation, and therefore have a high incidence of
negative side effects. There is a critical need to better understand the basic biology of the parasite in order to
ultimately design improved intervention and treatment strategies. Flagellated trophozoites proliferate to colonize
the intestine where cues including cholesterol starvation and increased pH at the end of the intestinal tract
promote terminal differentiation into cysts that detach for transmission. While current treatments target the
flagellated trophozoites, encystation could be exploited to clear Giardia infections. The regulation of encystation
is poorly understood across the diversity of encysting parasites; thus, studies focused on the encystation
pathway are of fundamental cell and developmental biology interest, as well as profound clinical relevance.
 The aim of this proposal is to understand how encystation cues are perceived and transduced to initiate the
encystation program. Our preliminary studies indicate that elevated cAMP is necessary to activate encystation.
Our preliminary studies identified a role for Giardia’s sole Rho family GTPase, GlRac, in the regulation of
cAMP. Protein-protein interaction studies with GlRac identified a previously uncharacterized seven-
transmembrane PQ-loop protein that belongs to the TOG (transporter/opsin/GPCR) superfamily. Knockdown of
this protein results in increased encystation indicating that it negatively regulates encystation. We named this
protein EncystR for its role in encystation. EncystR localizes to the plasma membrane in actively growing cells,
but exposure to encystation stimuli (high pH and cholesterol depletion), causes rapid internalization. EncystR
internalization requires GlRac, supporting a functional relationship between these proteins. EncystR negatively
regulates encystation through control of cAMP levels, but the mechanism remains to be determined. Related
PQ loop proteins are multi-function amino acid transporter-receptors that are known to be pH responsive and
can regulate development. EncystR is an exciting new entry point into uncovering the regulation of Giardia’s
developmental program.
 The overall goal of this project is to delineate the roles of EncystR and GlRac in regulating cAMP and
the role of cAMP in eliciting the encystation program. This work will establish a framework for understanding
the regulation of encystation from signal detection to encystation. Ultimately, we a...

## Key facts

- **NIH application ID:** 10604084
- **Project number:** 1R01AI168417-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Alexander Richard Paredez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $515,942
- **Award type:** 1
- **Project period:** 2022-09-19 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10604084

## Citation

> US National Institutes of Health, RePORTER application 10604084, Signal perception and transduction regulating Giardia cyst formation (1R01AI168417-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10604084. Licensed CC0.

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