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The SAInI Lab: Understanding Signalling networks in living cells

The department of MRDG, Indian Institute of Science, houses the SAInI lab, a clever acronym that stands for Signalling in Ageing, Inflammation and Infection, the three paradigms that Dr. Deepak Saini and his group work on.

Cellular signalling, a process that is gathering increasing attention in today’s scientific community, can be considered analogous to the extensive connectivity developed in our society, from the behemoth of the internet to the nondescript village post office. Today, these technologies hold the world together; in a similar way, cell signalling, with its diversity, extensive nodes and networks and clockwork precision enable every living cell to maintain a semblance of order among the multitude of chemical reactions that need to be controlled spatially and temporally to ensure that the cell remains alive.

While there are tens of signalling modes, hundreds of different types of molecules and thousands of connections that spread across time and space in the life of a single cell, all ‘signal transduction’ as the process from signal to response is called, utilizes a few common types of molecules that constitute a signalling pathway. The stimulus (signal) binds to a ‘receptor’ protein, usually present on the membrane of a cell. The now active receptor binds to molecules called transducers which amplify the signal and activate effector molecules. The effector molecules then induce a cellular response, mostly by binding to the genetic material or DNA of the cell and causing different proteins to be manufactured. This step by step transmission of a signal from its source to its receiver is called signal transduction.

What complicates this entire cascade is the fact that there are multiple types of receptors, sometimes common to a stimulus. An active receptor can recruit several different kinds of transducer molecules, each with their own set of effector molecules to interact with. The myriad of effector molecules that are now activated produce multiple and varied responses, both in terms of the type of proteins produced and when these proteins are produced.

It is within this intricate meshwork of signals and responses that the lab searches for answers to problems that plague current healthcare.

Ageing, along with its spectrum of age-related disorders like Alzheimer’s, heart disease and a weakening immune system to name a few, is now known to be regulated by specific signalling events inside cells. The SAInI lab focuses on a class of receptors known as GPCRs and their roles in the cascade of events which occur when a single cell grows old.

The same class of receptors, GPCRs are involved in almost all aspects of cellular function and are the targets of close to 40% of the drugs sold in the market. Receptors, however, do not work in isolation, and the lab is keenly pursuing the mechanisms by which receptors of different classes cross paths, a phenomenon known as ‘cross-talk’ and the ramifications of such cross-talk in the context of a cellular response. This body of work is expected to impact our understanding of complex processes like inflammation, where the cell produces chemicals that are very essential in low amounts, but are potentially harmful in chronic conditions.

Similar to ‘eukaryotic cells’ such as mammalian cells, ‘prokaryotic’ bacterial cells also possess an extensive internal network of connections that direct specific responses to specific stimuli. The SAInI lab is interested in one prokaryotic organism in particular, called Mycobacterium tuberculosis (Mtb). As the name suggests, this pathogenic micro-organism is responsible for the disease of tuberculosis, currently ranked second in terms of the number of deaths cause by a pathogenic organism worldwide. The lab studies cross-talk as well as insulated or specific signalling cascades that modulate the behaviour of Mtb. These studies provide insights into the mechanisms by which Mtb manipulates and as a consequence survives inside its host cell.

Traditionally, molecular biologists have studied cell signalling in isolation in test tubes (in vitro latin for ‘in glass’). This is done by purifying the components of a signalling cascade and studying how they interact with each other in vitro. A major caveat in these studies is that signalling in a cellular context is hardly ‘pure’ and there are innumerable stores and sinks inside a cell that can soak up or amplify a signal or simply change it in tens of different directions. To overcome this major roadblock, the SAInI lab utilizes cutting edge techniques that study signalling cascades in vivo (latin for ‘in the living’) in real time. Using these ‘imaging techniques’ which maintain a difficult balance between probing the microscopic environment of a cell and keeping a cell healthy and alive, the group of researchers under Dr. Deepak Saini have been able to record events that occur inside cells in millisecond timescales as well as monitor multiple parameters of receptors, transducers and effectors simultaneously, an essential requirement given the extensively branched pathways that a single receptor can activate.

Using a variety of in vitro and in vivo techniques, the SAInI lab have uncovered hitherto unknown links between signalling molecules, which have led them to explain key observations and make new predictions regarding cellular behaviour during the processes of Ageing and Inflammation. They have also discovered interesting features of Mtb that have improved our understanding of the disease process and in future could open up new avenues for targeting this dangerous human pathogen.

For prospective students, the SAInI lab offers a view into the dynamics of signalling networks inside live cells. Live Cell Imaging, Dr. Saini says, is sure to get students hooked, because “Seeing is Believing”.

About the lab

Deepak Saini is an Assistant Professor at the Department of Molecular Reproduction, Development and Genetics, IISc.

http://mrdg.iisc.ernet.in/dsaini/index.html

Tel : +91  80  22932574; Email: deepak@mrdg.iisc.ernet.in

 

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