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Molecular mechanism of juvenile hormone action in mosquito reproduction

Award Number: R01AI099250
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2012
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Molecular mechanism of juvenile hormone action in mosquito reproduction - Project Summary Mosquitoes are responsible for the transmission of many infectious diseases such as malaria, dengue fever, and Zika virus. Vector control using insecticides is currently the primary means of preventing the transmission of these diseases. In light of the rapid spread of insecticide resistance in mosquito populations, it is imperative to add new insecticides with different modes of action to the arsenal of mosquito control agents. The juvenile hormone (JH) signaling pathway is an attractive target for the control of mosquito vectors. JH is a key regulator of mosquito development and reproduction. Exposure of adult mosquitoes to pyriproxyfen, a synthetic JH mimic, has shown promise to effectively sterilize female mosquitoes. Our goal of this project is to elucidate the molecular pathways utilized by JH and its mimics to modulate mosquito fecundity. Mosquito egg development is mainly governed by JH and 20-hydroxyecdysone (20E). In the last funding cycle, we demonstrated that the Methoprene-tolerant (MET) protein is an intracellular receptor of JH. Both natural JH and pyriproxyfen binds to Aedes aegypti MET with high affinity. Upon binding of JH, MET forms a dimer with Taiman, a transcriptional factor that is involved in both JH and 20E responses. The MET-Taiman complex directly regulates the expression of JH-controlled genes. Besides the genomic action, we also reported a rapid JH signaling that is initiated from the plasma membrane. The non-genomic action, which relies on receptor tyrosine kinases (RTK), modulates the DNA-binding of the MET-Taiman complex and regulates the alternative splicing of the taiman gene. While the membrane-initiated JH signaling plays critically important roles in mosquito reproduction, the membrane JH receptor and the specific RTK have not yet been identified in mosquitoes. Our recent study demonstrates that a small portion of MET is associated with the plasma membrane in mosquito cells. Furthermore, depletion of MET eradicates the JH-activated increase in intracellular Ca2+, which is part of extranuclear JH signaling. Thus, our results suggest that the membrane- associated MET acts as a membrane JH receptor to mediate the non-genomic action of JH. In this proposed study, we will test the hypothesis that the JH action in mosquitoes is mediated by both membrane-bound and nuclear MET proteins, and that pyriproxyfen uses this JH signaling pathway to inhibit 20E-regulated gene expression. In Aim 1, we will define the roles of membrane MET in the membrane binding of JH and the membrane-initiated JH signaling. In Aim 2, we will investigate how membrane MET mediates the nongenomic action of JH in mosquitoes. In Aim 3, we will elucidate how pyriproxyfen utilizes the JH signaling pathway to suppress the vitellogenic 20E response. This study will add a new dimension to our understanding of the JH signaling pathway that is required for mosquito reproduction. It may also reveal new targets in the JH signaling pathway that can be exploited for pesticide development.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $387,570 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	9	2/28/2025	NON-COMPETING CONTINUATION	$387,570
														Subtotal = $387,570

Issue Date FY: 2024 ( Subtotal = $411,610 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	8	5/23/2024	NON-COMPETING CONTINUATION	$41,161
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	8	2/21/2024	NON-COMPETING CONTINUATION	$370,449
														Subtotal = $411,610

Issue Date FY: 2023 ( Subtotal = $40,143 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	7	3/3/2023	NON-COMPETING CONTINUATION	$40,143
														Subtotal = $40,143

Issue Date FY: 2022 ( Subtotal = $403,604 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	6	2/24/2022	NON-COMPETING CONTINUATION	$403,604
														Subtotal = $403,604

Issue Date FY: 2021 ( Subtotal = $399,726 )
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	5	3/16/2021	COMPETING CONTINUATION	$399,726
														Subtotal = $399,726

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	4	6/5/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $342,426 )
2015	2015	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	460 TURNER STREET, SUITE 306	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	4	1/1/2015	NON-COMPETING CONTINUATION	$342,426
														Subtotal = $342,426

Issue Date FY: 2014 ( Subtotal = $343,802 )
2014	2014	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	460 TURNER STREET, SUITE 306	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	3	6/6/2014	NON-COMPETING CONTINUATION	$34,380
2014	2014	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	460 TURNER STREET, SUITE 306	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	3	1/7/2014	NON-COMPETING CONTINUATION	$309,422
														Subtotal = $343,802

Issue Date FY: 2013 ( Subtotal = $324,362 )
2013	2013	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	460 TURNER STREET, SUITE 306	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	1/4/2013	NON-COMPETING CONTINUATION	$310,559
2013	2013	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	460 TURNER STREET, SUITE 306	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	2	6/6/2013	NON-COMPETING CONTINUATION	$13,803
														Subtotal = $324,362

Issue Date FY: 2012 ( Subtotal = $328,345 )
2012	2012	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	460 TURNER STREET, SUITE 306	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	1/27/2012	NEW	$328,345
														Subtotal = $328,345

Grand Total All Awards = $2,981,588

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Molecular mechanism of juvenile hormone action in mosquito reproduction

Award Number: R01AI099250

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2012

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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