The damaging effect of mosquito-borne diseases is colossal, with about a million deaths and hundreds of thousands of people becoming seriously ill annually. Being the principal vector for dengue, yellow fever, chikungunya virus and recently Zika virus, the Aedes aegypti mosquito is an extremely important organism for investigation. Small non-coding microRNAs (miRNA) are responsible for posttranscriptional control of mRNAs and act as essential regulators of development. Our efforts during the previous funding cycle have revealed the role of miRNAs in controlling multiple physiological functions in female mosquitoes. Moreover, we have established a number of essential methodologies for mosquito miRNA investigations, from bioinformatics and miRNA library sequencing to genetics approaches such as CRISPR/Cas9 and GAL4/UAS. These studies have provided a foundation for further exploration of mosquito miRNAs. However, our knowledge about miRNA roles in such an essential process as female mosquito reproduction is still limited. Thus, the goal of the present grant proposal is to elucidate the involvement of miRNAs in regulatory networks governing blood-meal-activated reproductive events in female mosquitoes. The overall hypothesis is that miRNAs are critical components of these regulatory networks. We will examine the following hypotheses in Specific Aims:
Aim 1. miRNAs are involved in posttranscriptional regulation of enzymes essential for blood digestion.
Aim 2. miRNAs are required for the control of key factors of transcriptional networks that are necessary for orchestrating the female mosquito reproductive cycle.
Aim 3. As important regulatory molecules, miRNAs are under strict control, coordinating their activity with demands of mosquito reproduction. The innovation of this proposed research rests on a comprehensive analysis of the role of miRNAs in mosquito reproduction and application of wide-ranging methodologies, such as CRISPR-Cas9 and Gal4-UAS. The significance of the present grant proposal is in establishing a novel paradigm concerning the association of miRNAs with regulatory networks controlling mosquito reproduction.

Public Health Relevance

Alexander S. Raikhel . NARRATIVE The present proposal aims to establish a novel paradigm concerning the association of microRNAs with regulatory networks controlling mosquito reproduction and to test the hypothesis that miRNAs are critical components of these regulatory networks. Mosquito-borne diseases pose an enormous problem, and studying mosquito reproduction is highly relevant to public health because it provides a foundation for vectorial capacity. By utilizing such methodologies as bioinformatics, miRNA library sequencing and the genetics approaches CRISPR/Cas9 and GAL4/UAS, the proposed research promises to change our understanding of the molecular basis of female mosquito reproduction significantly.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI113729-06
Application #
9740204
Study Section
Vector Biology Study Section (VB)
Program Officer
Costero-Saint Denis, Adriana
Project Start
2014-06-15
Project End
2024-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Zoology
Type
Earth Sciences/Resources
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
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Ling, Lin; Kokoza, Vladimir A; Zhang, Changyu et al. (2017) MicroRNA-277 targets insulin-like peptides 7 and 8 to control lipid metabolism and reproduction in Aedes aegypti mosquitoes. Proc Natl Acad Sci U S A 114:E8017-E8024
Zhang, Yang; Zhao, Bo; Roy, Sourav et al. (2016) microRNA-309 targets the Homeobox gene SIX4 and controls ovarian development in the mosquito Aedes aegypti. Proc Natl Acad Sci U S A 113:E4828-36
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Lucas, Keira; Raikhel, Alexander S (2013) Insect microRNAs: biogenesis, expression profiling and biological functions. Insect Biochem Mol Biol 43:24-38