DESCRIPTION (provided by applicant): Mosquito-transmitted parasitic diseases are among the major causes of mortality and morbidity in the world. Recent dramatic increases in the incidence of mosquito-borne diseases, like Malaria, Chikungunya and Dengue Fever, and the wide-spread resistance of mosquitoes to insecticides underscores the need for new approaches for insect control based on mosquito-specific agents. The discovery of such mosquito-specific control agents depends on continued basic research on the biology of mosquitoes. Juvenile hormone (JH) is a major hormonal regulator in insects. In the female mosquito, JH signals the completion of the ecdysis to the adult stage, and initiates reproductive processes. JH titer is essentially determined by the rate at which the corpora allata (CA) synthesizes JH. Our research, using an integrative approach that combines experiments at the organismal, cellular and molecular level, is revealing that mosquito regulation of JH synthesis has unique features that are related to the adaptation to blood-feeding and the cyclic regulation of ovarian development. We have described that the CA of the female mosquito alternates between periods of high and low biosynthetic activity that are linked to developmental programs and nutritional signals. We have identified neuropeptides that stimulate or inhibit JH synthesis and have characterized their receptors. We have performed the first genomic analysis of an insect endocrine gland and studied the expression of all the JH biosynthetic enzymes. We have also described that nutrients accumulated during the larval stages regulate CA activity and developed a unique model of nutritionally deficient mosquitoes that do not synthesize JH. The goal of this project is to understand the role and mechanism of action of the different factors tha control CA activity (allato-regulatory factors). We also seek to identify the rate limiting steps ad regulatory points of JH synthesis. To accomplish these goals, we will focus on three key stages: 1) The developmentally- and nutritionally-dependent activation of JH synthesis in the CA of newly eclosed adult females, 2) The nutritionally-dependent modulation of JH synthesis in mature sugar-fed females and 3) The suppression and reactivation of JH synthesis after blood-feeding. These three stages are critical moments in the reproductive maturation of mosquitoes and make excellent experimental models that are also relevant for disease control. These areas of research should identify targets for designing new, specific and affordable chemical strategies suitable for mosquito control in developing countries.

PUBLIC HEALTH RELEVANCE: New approaches are needed for vector control of mosquito-borne diseases such as Dengue fever, Chikungunya and Malaria that are critical threats to public health in many parts of the world. The discovery of mosquito-specific control agents depends on continued basic research on the biology of mosquitoes. Juvenile hormone (JH) is a major hormonal regulator that controls development and reproduction in mosquitoes; and this application aims to understand the unique features of JH synthesis in mosquito and identify targets for designing new, specific and affordable chemical strategies suitable for mosquito depletion or incapacitation in endemic areas.