Unraveling Fibrosis: Trailblazing Research and Its Impact

Fibrosis, the formation of excess connective tissue, is a devastating condition that affects millions of people worldwide and, overall, accounts for ~45% of the health care costs and deaths in the developed world. Its underlying mechanisms have remained elusive, and thus there are limited treatment options. Working at the University of Saskatchewan under the supervision of Professor Andrew Leask, Pratyusha Chitturi is making remarkable strides in unraveling this complex puzzle. Her work not only focuses on the mechanisms underlying scleroderma, a debilitating autoimmune connective tissue disease that can result in poor oral hygiene and tooth loss, but also provides insight into and hope for the entire range of fibrotic diseases, that include cancers, diabetes, pulmonary fibrosis, and fatty liver disease. Today we explore the groundbreaking research conducted by PhD student Pratyusha Chitturi and the potential impact it may have on society, the economy, and healthcare.

The Quest for Answers

Chitturi's research is centered on scleroderma (from the Greek “scleros” and “derma”, meaning “hard” and “skin”, respectively), a disease characterized by progressive fibrosis of the skin and internal organs, which can severely impair the ability to perform routine physical activities. Scleroderma affects approximately 1 in 10,000 individuals, mostly women between the ages of 30 to 50.  The core question driving her work is to understand the fundamental mechanisms underlying fibrosis, using scleroderma as a model system. Specifically, she seeks to use state-of-the-art bioinformatics approaches to identify the specific cells, pathways, and genes responsible for this condition. Importantly, her research extends beyond scleroderma and offers the promise of improved treatments and potential cures for all fibrotic conditions, in general.

What Drives Pratyusha Chitturi?

What motivates Pratyusha Chitturi, with unwavering determination, to pursue this research? The answer lies in the devastating impact of fibrosis on quality of life of those affected. With no cure in sight, patients with fibrotic diseases face ongoing suffering, and, in the case of severe so-called diffuse scleroderma, even death, largely due to lung disfigurement. This motivation drives Chitturi to seek innovative solutions and explore new avenues of research.

One exciting aspect of her work is the use of spatial transcriptomics, an innovative approach that enables the identification of genes within individual skin cells responsible for fibrosis. This bioinformatics technique not only allows her to delve into the intricate molecular processes but also to visualize and present her data in a variety of engaging and informative ways. Her fascination with transcriptomics and her use of computer programming languages like R exemplify her dedication to advancing scientific understanding.

Key Findings

Chitturi's research has already yielded significant findings. Fibrotic cells are located within scar tissue. Collectively, the fibrotic cells and scar tissue act upon each other to produce a stiff environment. Professor Leask says: “prior to Pratyusha conducting her studies, our lab has been at the forefront of showing that this stiff environment is both necessary and sufficient for fibrosis. Once this stiff environment starts, the tissue is in an endless loop that is responsible for persistence of the scar tissue. A protein, a so-called transcriptional cofactor, called YAP1 is responsive to and responsible for this endless loop.” Chitturi has discovered that compounds such as celastrol, which antagonize YAP1, could be potential treatment options for skin fibrosis in systemic sclerosis (SSc). Celastrol's specific effect on a particular type of skin cells, called reticular fibroblasts, holds promise for targeted treatments in the future.

Impacts on Society and the Economy

The potential impact of Chitturi's research is profound and far-reaching. It provides valuable insights into specific fibroblast types responsible for fibrosis, potentially leading to more effective treatments and prevention strategies. This research is especially significant for severe scleroderma cases, where major organs such as the oral cavity, esophagus, heart, lungs, and kidneys are affected. Diffuse scleroderma patients that have lung involvement, which represent ~80% of all cases, have a disease-related survival rate of approximately 50% over ten years, highlighting the urgent need for better treatments.

Beyond its impact on healthcare and patients' lives, her research also holds the potential to stimulate economic growth. New treatments and diagnostic tools for fibrotic diseases could lead to a thriving biotech industry, providing employment opportunities and contributing to the overall economy. Proffessor Leask further states: “My colleagues and I are currently developing a ‘next-generation’ drug that works in the YAP cascade, but may be more specific. We are currently working on securing funding for this project and are in the process of filing an Investigational New Drug Application for this drug in the US. Pratyusha’s work is essential for providing an intellectual framework for our studies.”

Publication and Collaboration

Chitturi's research has not only been groundbreaking but also transparent and well-documented. Her work has been published in the "Annals of Rheumatic Diseases", the top research-oriented journal in Rheumatology, under the title "Tripterygium wilfordii derivative celastrol, a YAP inhibitor, has antifibrotic effects in systemic sclerosis." This publication serves as a valuable resource for researchers and clinicians interested in the field.

Collaboration has played a crucial role in her research journey. She worked with scholars and experts from various universities, including the University of Calgary and Western University, and, notably, the Royal Free Hospital, affiliated University College London. “Our collaboration with the Rheumatology clinic at the Royal Free Hospital, which has been ongoing for ~25 years, was essential for using patient-derived material to give a real-life validation of her results”, continues Dr Leask. These interactions allowed her to access diverse data, techniques, and data analysis software, which enriched her research and contributed to the comprehensive, translational nature of her findings.

A Personal and Professional Journey

Chitturi's research journey has been a source of pride and personal growth. She openly acknowledges the initial challenges and feelings of intimidation. Still, through perseverance and dedication, she has made significant strides in the field of fibrosis research. Her work serves as a testament to the power of determination and collaboration, showing that even the most complex scientific questions can be answered with the right combination of skills, innovation, and dedication. “Her initiative, dedication and drive were essential for the progress and success of this project,” said Prof. Leask.

Chitturi's research at the University of Saskatchewan offers hope for those affected by fibrotic diseases and opens the door to a better understanding of the mechanisms underlying these conditions. Her dedication, innovative techniques, and collaborations pave the way for future breakthroughs, promising improved treatments, and potentially life-saving solutions. With her groundbreaking work, Chitturi is leading the charge in the fight against fibrosis, bringing us one step closer to a future free from its devastating grip.