Research

Research in my lab takes advantage of the sophisticated genetic tools available in the model organism Drosophila to better understand and dissect the underlying mechanisms of normal development and disease. We are particularly interested in understanding the contributions of Extracellular Matrix to normal development and tumorigenesis. Development of Drosophila wing is another area of my labs’ interest as this is an excellent model for organogenesis where various events that give rise to an adult structure can be studied.   Several projects spanning the domain of our interest are available for motivated students. 

Basement Membranes and their Role in Development and Disease

The Basement Membrane (BM) is a specialized form of Extracellular Matrix that surrounds several organs and tissues. It is evolutionarily conserved and is made up of several proteins like Collagen, Laminin, Nidogen and Proteoglycans. Throughout development the BM is formed and degraded in a process called remodeling. Several proteases like the Matrix Metalloproteases (MMPs) have been implicated in this remodeling. Indeed, knockdown of MMPs result in developmental defects in the fly. In addition to development, BM remodeling is also observed during the progression of tumors from a benign to a metastatic state. This hallmark of tumor metastasis is mediated by MMPs as well. It is believed that BM degradation releases signaling molecules into the surrounding milieu which influence cellular behavior. The Srivastava Lab is focused on understanding the contributions of BM to normal development and tumor metastasis. To better understand the biology of BM we have focused on three aspects. 1) We conducted a genetic screen to identify novel degraders of BM. We are currently characterizing the candidate BM degraders. 2) Utilizing a biochemical approach we isolated binding partners of BM and identified them using Mass Spectrometry. We are beginning to characterize the binding partners. 3) We are also attempting to understand the role of proteases other than MMPs in development and disease pathogenesis. 

Organ Development in Drosophila

The thoracic air sacs in Drosophila are analogous to human lungs in that they supply Oxygen to the flight muscles. Development of the thoracic air sacs begins at the start of third larval instar where a group of tracheal cells begin to proliferate and migrate in response to FGF signaling. These cells form the Air Sac Primordium (ASP) which  eventually occupies a deeper position in the wing imaginal disc. The invasive behavior displayed here is similar to what is observed during the invasion by cancer cells. Srivastava Lab has recently demonstrated that a class of proteases called the Cathepsin L mediates this invasive behavior. Consequently knockdown of the Cathepsin L results in a superficial position of the ASP. We also demonstrated that Cathepsin L mediates ASP invasive behavior by promoting the degradation of Basement Membrane. We are currently working on further teasing the role of Cathepsin L in ASP invasive behavior and organ development.

Air Sac Primordium from a Drosophila Third Instar Larva

Cathepsin L Expression in the ASP

Knockdown of Cathepsin L results in suppression of invasive behavior (C,D versus A,B)

Funding Acknowledgement

Research in the Srivastava Lab has been funded by: