First person – Kolaparamba V. Navyasree

Kolaparamba V. Navyasree

How would you explain the main findings of your paper in lay terms?

Every cell in our body needs nutrients and growth factors for growth and development. The cell must be able to properly sense these molecules. mTORC1 is a protein kinase complex known for its nutrient-sensing capacity. mTORC1 can sense nutrients like amino acids and growth factors like insulin; based on their availability, it can trigger cellular activity for growth and development. In our study, we discovered that cholesterol, a component of cell membranes, can regulate insulin-mediated mTORC1 sensing and signaling activities. Individuals with a disease condition called Smith–Lemli–Opitz syndrome (SLOS) have problems with cholesterol synthesis. We also found that insulin-induced mTORC1 signaling was altered in cells from individuals with SLOS, leading to cellular growth defects. We could rectify these defects by externally providing cholesterol or mTORC1 activators to the SLOS cells. This, we think, opens a new perspective for identifying the mechanisms underlying the developmental issues in individuals with SLOS as well as for designing treatment strategies.

Were there any specific challenges associated with this project? If so, how did you overcome them?

The first and foremost challenge was to understand cholesterol-mediated mTORC1 signaling in different cell lines. Because cholesterol is an integral component of cell membranes, acute removal of cholesterol often leads to cell death. To overcome that, we standardized the proper amount of methyl-β-cyclodextrin and the duration of treatment to be used in each experiment, along with the amount of cholesterol needed for rescue.

Another major challenge was to understand the signaling mechanisms in the skin fibroblasts from individuals with SLOS. The skin fibroblast cells were slow growing and hard to maintain in cultures, and it was difficult to obtain proper readouts from immunofluorescence experiments. These factors were delaying the whole project, so we generated a pharmacological SLOS model in parallel using HeLa cells to confirm our findings.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

Our initial goal was to try to understand the insulin-cholesterol axis of mTORC1 signaling. Later, when we delved into the disease-related aspects of the study, we could see that this axis is altered in SLOS cells, confirming the insights from our basic findings in a disease context. Furthermore, we realized that currently there are no effective treatment options for SLOS patients. When we tested our hypothesis by adding cholesterol or Rag GTPase, it restored normal mTORC1 signaling in SLOS cells. This indicated that it might be possible to correct the mTORC1 signaling defects in individuals with SLOS and became the major eureka moment that led to a meaningful research story.

Why did you choose Journal of Cell Science for your paper?

We wanted our novel data regarding cellular signaling to be noticed in a relevant research environment. Journal of Cell Science is a reputable cell biology journal with a wide audience and a wonderful editorial team, which makes it a highly appropriate platform for publishing our exciting findings.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

My supervisor, Dr Perunthottathu K. Umasankar, played a pivotal role in my research journey by providing invaluable mentorship, expert guidance and unwavering support throughout the research process. His expertise significantly contributed to the success and quality of my research work. I would also like to mention Prof. Chandrabhas Narayana, Dr Mahak Sharma, Dr T. R. Santhosh Kumar and Dr K. B. HariKumar who are all part of my Doctoral Advisory Committee (DAC) for providing me with invaluable suggestions throughout my research.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

Biology is a field that continually presents intellectual and technical challenges and opportunities for problem solving. I was deeply interested in pursuing higher studies in biology, especially after my master’s degree. I had a very keen interest toward studying cells – the fundamental units of life – and the underlying molecular mechanisms they use to grow and survive. Owing to all the summer research training I had from some of the most prestigious labs in India, I believed that getting my PhD would be a great choice towards fulfilling my dream. My research thereafter fulfilled my dream of seeing and understanding cells from a closer perspective.

Who are your role models in science? Why?

Ever since I started learning about the basics of science, all the major scientific discoveries and scientists have inspired me. Eminent scientists like Rosalind Franklin, Marie Curie, Albert Einstein, Nikola Tesla, etc.

What's next for you?

I want to continue my research in cell biology after completing my PhD. I am thrilled to explore more about the mechanisms of cellular signaling and to understand more about the mysteries of the basic unit of life.

Tell us something interesting about yourself that wouldn't be on your CV

I love food, travel and zoneing out, just being myself.