There has been a continuous demand for the development of insect control methods that are target-specific. Juvenile hormone (JH) and ecdysteroids are the major hormones that regulate development and reproduction in insects. Since these hormones are not present in vertebrates, they represent attractive targets for the development of insect control methods. Hindering this effort is the lack of understanding on the molecular basis of JH action. Tremendous progress has been made in understanding JH action at the molecular level during the past few years. A bHLH transcription factor, methoprene tolerant (Met), has been identified as a JH receptor. A steroid receptor co-activator homologue (SRC/Taiman/FISC) and Cycle have been identified as important co-factors involved in JH action. Kruppel homologue (Kr-h1) and bHLH transcription factor, Hairy and E93 have been identified as important transcription factors that mediate JH action. Preliminary experiments showed that Cyclic AMP response-element binding protein (CBP) is required for acetylation of histone H3 as well as for JH induction of JH-response genes in Tribolium castaneum tissues, TcA and Aag-2 cells. In addition, histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA) also induces expression of JH-response genes in TcA and Aag-2 cells. Chromatin modifiers Brahma, Snr1 and CHD1 but not DNA methyl transferase are required for regulation of metamorphosis and reproduction in T. castaneum. JH exerts diverse functions in different tissues and under various physiological conditions. We hypothesize that epigenetic and post- translational modification of proteins involved in JH action play critical roles in multi-dimensionl gene regulation strategies employed by JH. Therefore, the main objective of this proposal is to capitalize on these latest developments to identify epigenetic modifiers and determine their mechanisms of action in modulation of JH response using T. castaneum, TcA and Aag-2 cells. The two Specific Aims of the proposal are 1. To identify key players involved in epigenetic and post-translational modifier regulation of JH action and 2. To determine the mechanisms involved in epigenetic and post-translational modifier regulation of JH action. In the first Specific Aim, w will employ RNAi, cell culture and reporter assays to identify and characterize key proteins including histone acetyl transferases (HAT), HDACs and chromatic modifiers involved in modulation of JH action. Temporal, spatial and hormonal regulation of identified genes as well as their function in JH action will be determined. In the second Specific Aim, we will employ mass spectrometry, RNAi, two-hybrid, pull- down, Chip and reporter assays to identify acetylated lysines in Met, domains of HATs, HDACs and Brahma, Snr1 and CHD1 required for JH action, localize HATs, HDACs and Brahma, Snr1 and CHD1 on Kr-h1, Hairy and E93 promoters and identify interacting partners of HATs, HDACs, Brahma, Snr1 and CHD1. The expected outcome of this study, an understanding of the molecular basis of JH action and identification of critical proteins involved in JH action will help in development of methods for control of insect vectors. The proposed studies will also advance our knowledge on epigenetic and post-translational modification of histones and other nuclear proteins especially on the functions and mechanisms of action of the modifiers.

Public Health Relevance

Mosquitoes transmit deadly diseases. The research proposed in this application will provide information of potential importance for development of insecticide for vector control. The proposed studies will reveal functions and mechanisms of action of epigenetic marks which will help in understanding epigenetics of human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM070559-11
Application #
9198017
Study Section
Vector Biology Study Section (VB)
Program Officer
Chin, Jean
Project Start
2005-02-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
11
Fiscal Year
2017
Total Cost
$252,000
Indirect Cost
$72,000
Name
University of Kentucky
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Palli, Subba Reddy (2017) New roles for old actors, ROS and PRMT1. Proc Natl Acad Sci U S A 114:10810-10812
Roy, Amit; George, Smitha; Palli, Subba Reddy (2017) Multiple functions of CREB-binding protein during postembryonic development: identification of target genes. BMC Genomics 18:996
Bai, Hua; Palli, Subba Reddy (2016) Identification of G protein-coupled receptors required for vitellogenin uptake into the oocytes of the red flour beetle, Tribolium castaneum. Sci Rep 6:27648
Gujar, Hemant; Palli, Subba Reddy (2016) Juvenile hormone regulation of female reproduction in the common bed bug, Cimex lectularius. Sci Rep 6:35546
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Gujar, Hemant; Palli, Subba Reddy (2016) Krüppel homolog 1 and E93 mediate Juvenile hormone regulation of metamorphosis in the common bed bug, Cimex lectularius. Sci Rep 6:26092
Das, Sumistha; Debnath, Nitai; Cui, Yingjun et al. (2015) Chitosan, Carbon Quantum Dot, and Silica Nanoparticle Mediated dsRNA Delivery for Gene Silencing in Aedes aegypti: A Comparative Analysis. ACS Appl Mater Interfaces 7:19530-5
Shukla, Jayendra Nath; Palli, Subba Reddy (2014) Production of all female progeny: evidence for the presence of the male sex determination factor on the Y chromosome. J Exp Biol 217:1653-5
Li, Zhiqian; Ge, Xie; Ling, Lin et al. (2014) CYP18A1 regulates tissue-specific steroid hormone inactivation in Bombyx mori. Insect Biochem Mol Biol 54:33-41
Cui, Yingjun; Sui, Yipeng; Xu, Jingjing et al. (2014) Juvenile hormone regulates Aedes aegypti Krüppel homolog 1 through a conserved E box motif. Insect Biochem Mol Biol 52:23-32

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