Life Sciences & Biotechnology
Title : | Deciphering the role of protein neddylation in malaria parasite and its targeting to block transmission |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Parasitology |
Principal Investigator : | Dr. Satish Mishra, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | satish.mishra@cdri.res.in |
Details
Executive Summary : | The study of malaria transmission is limited due to the lack of molecular details about its transition stages. Neddylation, a recent post-translational modification, plays a critical role in higher organisms but remains unknown in the malaria parasite. A laboratory study found that parasites lacking NEDD8 failed to transmit malaria from mammalian hosts to mosquito vectors and did not form oocysts. To determine stage-specific defects, the researchers investigated the formation of ookinetes and gametocytes and found that NEDD8 knockout parasites produced gametocytes but failed to form ookinetes. The study aims to study the infectivity of sporozoites lacking NEDD8 and its conjugating enzyme UBC12 in hepatocytes. Conditional KO (cKO) parasites will be generated using the Flp/FRT recombination system to study their role beyond mosquito stages. If these cKO parasites completely lack hepatocyte infectivity, they will be established as a multistage drug target. The project has six objectives: 1) Demonstrate Plasmodium UBC12 is a NEDD8-conjugating enzyme; 2) Generate UBC12 KO parasites and conduct detailed phenotypic characterization; 3) Generate conditional KO (cKO) parasites to analyze parameters associated with infection, gliding pattern, cell traversal activity, ability to invade cells, development, and progression through liver stages; 4) Generate NEDD8 or UBC12 -3XHA-mCherry transgenic parasites to study expression and localization; 5) Understand the mechanistic aspect of NEDD8 and UBC12 KO parasites phenotype through transcriptomic and ultrastructural studies of gametocytes; and 6) Focus on drug discovery and development against UBC12. |
Co-PI: | Dr. Mrigank Srivastava, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh-226031 |
Total Budget (INR): | 43,95,000 |
Organizations involved