Study location	Türkiye, Istanbul
Type	Summer Research Program - Graduate, full-time

Language requirements	English

Other requirements	At least 2 reference(s) must be provided.

Overview

“Aim of this project is to develop a novel and specific inhibitor targeting mitochondrial fission machinery which plays role in development and progression of cancer, diabetes and neurodegenerative diseases. Mitochondria is considered as an organelle responsible for energy production through oxidative phosphorylation in cell. Today besides its energy production mitochondria also participates in many different physiological processes such as programmed cell death, mitophagy, redox signalization and calcium homeostasis. Mitochondria is a highly dynamic organelle responding to cellular stress conditions through mitochondrial mass alterations, fusion and fission and location changes in cell. Mitochondrial fusion can be explained by mitochondria’s forming an elongated mitochondrial network and vice versa small fragmented mitochondria’s are formed by mitochondrial fission. Mitochondrial functions and mitochondrial dynamics (fission and fusion) has an important role in understanding the biological processes like apoptosis and aging and molecular mechanisms of many diseases such as obesity, diabetes, complex diseases like Parkinson’s and Alzheimer’s and cancer. Recent studies revealed that cancer cells alter mitochondrial dynamics (increase mitochondrial fission protein, Drp1) to gain resistance against apoptosis and regulate bioenergetics and biosynthetic requirements to support proliferation, migration and therapeutic resistance acting on tumor origination and transformation characteristics. It has been reported that at type 1 diabetes and neurodegenerative diseases Drp1 expression was increased. Therefore, development of new inhibitors targeting mitochondrial fission become important for improving treatment of diseases which mitochondrial dynamic alteration processes act and for studying biology of mitochondrial dynamics.
This project mainly comprises of two parts. In first part mitochondrial fission inhibitor design will be performed by computational methods. Target inhibitor molecule will inhibit the interaction between Drp1 and mitochondrial outer membrane proteins, which carry and localize Drp1 to mitochondria outer membrane, MiD49/51. MiD49 and MiD51 cytosolic regions and MiD49/Drp1 complex structures have been revealed by experiments. Therefore, structure-based drug design approaches will be used in this project to design inhibitor molecules. Candidate molecules for bioactivity tests will be determined by virtual screens of 3.6 million molecules with docking calculations. At second part effects of synthesized inhibitor molecules on Drp1-MiD49/51 protein interactions and mitochondrial fission will be studied. In this context effect of the inhibitors will be studied by using confocal and real time fluorescent microscopes. Effects of new Drp1-MiD49/51 inhibitors on mitochondrial functions will be tested by mitochondrial membrane potential, oxygen consumption rate, mitochondrial complex activities, cellular reactive oxygen species, cell viability and apoptosis studies. Lastly effect of developed inhibitors on receptor-ligand kinetics of Drp1-MiD49/51 will be studied. Developing a new inhibitor for MiD49/51 and Drp1 interaction has a great importance of being novel and specific and also has a drug potential. Accomplishing the aims of this project will also help our country to take part in this field in international arena.”