Principal Investigator/Program Director (Last, first, middle): Han, Zhe RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? m Yes l No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes m No IACUC Approval Date: Animal Welfare Assurance Number 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 6931-Han-Abstract.pdf Mime Type: application/pdf 7. * Project Narrative 3733-Narrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 9486-Han_Reference.pdf Mime Type: application/pdf 9. Facilities &Other Resources 1953-resources.pdf Mime Type: application/pdf 10. Equipment 7434-Major_Equipment.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Han, Zhe Abstract The early morphogenetic mechanisms involved in heart formation are evolutionarily conserved. To identify novel cardiogenic genes, we performed a large-scale genetic screen in Drosophila. We discovered a unique cardiac defect, called broken hearted (bro), in which pericardial cells and cardioblasts dissociate, causing loss of cardiac function and embryonic lethality. This phenotype resulted from mutations in genes encoding HMG-CoA reductase and its downstream enzymes in the mevalonate pathway, as well as G protein G?1, which is geranylgeranylated, thus representing an end point of isoprenoid biosynthesis. Identification of the essential role of C in cardiac morphogenesis opened a door to discovery of the entire G protein genetic pathway required for cardiac morphogenesis. Here, we will investigate the functional mechanism of G?1, and identify the G? and G? partners that form the cardiac heterotrimeric G protein complex with G?1. From our screen, we also identified two G-protein coupled receptors (GPCRs) involved in this process. We will investigate the roles of these GPCRs using cardiac cell type specific rescue system established in our preliminary studies. Our screen also identified two bro mutations disrupting genes encoding septate junction components, indicating that septate junction formation is involved in cardiac morphogenesis. We will characterize the cell-cell junctions of Drosophila heart using electron microscopy and study the role of septate junction proteins during heart development. We will also examine how the G protein signaling mutants affect septate junction formation in the heart. These studies will fill a significant gap in the research field of heart development, and promote our understanding of the molecular mechanism of congenital heart disease. Project Description Page 6
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