Research
Overview
Have you ever wondered why our hands never grow to touch our feet? For that matter, every organ in the body has a very specific size and form (patterning) for optimal function. In some cases, even a slight change in the size and shape can lead to serious health condition. For example, a slight defect in heart can often be lethal. Then the question is: how do the organs know when to stop growing? More importantly, you may be thinking why should we care about this question. It turns out that every cell in the body has an intrinsic mechanism to control growth, and when these mechanisms fail, they grow in an uncontrolled manner and give rise to cancer.
We seek to understand how tissue growth is precisely regulated during embryonic development and how dysregulation of this process result in devastating diseases such as cancer. We use the fruit fly, Drosophila melanogaster as a model organism to study how the Hippo signaling pathway and the protocadherins, Dachsous and Fat play an important role in tissue growth and patterning regulation. We also strive to understand how the Hippo pathway gets deregulated in cancers and develop novel chemical inhibitors for this pathway. We employ an interdisciplinary approach using genetics, cell biology, biochemistry and chemical biology.
Regulation of growth and morphogenesis during development
Proper size and shape is required for optimal functioning of organs. In multicellular organisms, different tissues develop to a characteristic final size and shape, and maintain an optimal proportion to the body. Misregulation of growth and morphogenesis during development results in structural birth defects that last into adulthood and often lead to organ malfunction. Thus precise coordination of growth and morphogenesis is a fundamental aspect of development that is essential for normal organ function and body organization. The evolutionarily conserved Hippo signaling pathway plays a central role in organ size control and is associated with many cancers. The protocadherins, Dachsous (Ds) and Fat are conserved upstream regulators of Hippo signaling that play a key role in coordinating growth and morphogenesis. Ds and Fat restrict growth by activating Hippo signaling and influence morphogenesis by regulating planar cell polarity and oriented cell divisions. Consistently, mutations affecting this pathway result in a number of diseases affecting organ shape or size, such as Hennekam syndrome and Van Maldergem syndrome. However, the molecular mechanisms by which Fat signaling regulates growth and morphogenesis are not well understood. I have identified Vamana and Early girl, two novel regulators of this signaling pathway. Additionally, my work has led to intriguing findings that suggest that vesicular trafficking plays a crucial role in regulating this pathway, an aspect that is very little explored. Our lab employs an interdisciplinary approach using Drosophila genetics, cell biology and biochemistry to study the vesicular trafficking mechanisms that organize this signaling pathway and to identify novel regulators of this pathway.
Ongoing projects include:
1. How is the spatial organization of the Ds-Fat signaling pathway established?
2. How Ds-Fat signaling regulates Hippo signaling?
3. How Fat signaling regulates organ shape?
Development of novel inhibitors of YAP activity for cancer therapy
The Hippo signaling pathway is evolutionarily conserved in humans, and the downstream effector of this pathway YAP/TAZ is frequently deregulated in most cancers and provides a nodal point for treatment. We take an interdisciplinary approach to understand how this pathway is deregulated in cancers and to develop inhibitorsof YAP activity. YAP/TAZ also plays a critical role in pulmonary fibrosis and YAP activity inhibitors have shown promising effect in treatment of this disease. So the YAP activity inhibitors we develop will also be useful for treatment of fibrosis.
Ongoing projects include:
1. To understand the basic mechanism by which the Hippo pathway is activated and deactivated.
2. To identify novel mechanisms by which YAP/TAZ gets deregulated in different cancers.
3. Development of small-molecule inhibitors of TEAD using computational and experimental methods.
4. Development of TEAD inhibitors by DNA-encoded library screening.
5. Development of Proteolysis Targeting Chimeras (PROTAC) for degrading TEAD.