The lab: Gotthardt group
Lab's research themes:
The long-term goal of the Gotthardt-lab is to develop a basic understanding of the transition from cardiovascular health to disease at the molecular, cellular, organ and systems level and use this information to improve patient care.
Specifically, we are interested in understanding how alternative splicing relates to diastolic heart failure, how increased filling of the cardiac ventricle leads to improved contraction (Frank-Starling mechanism of the heart), and how the electrical properties of the heart and mechanoelectrical coupling are regulated.
The group focuses on titin, the largest protein in the human body, and the multifunctional coxsackie- and adenovirus receptor (CAR). To lay the groundwork for the in vivo analysis of titin's multiple signaling, elastic, and adaptor domains, the group has generated various titin knock-in and conditional knockout mice and established a tissue culture system to study titin's striated muscle functions and sarcomere dynamics.
We utilize a combination of cell-biological, biochemical, genetic, pharmacological, and omics tools to establish titin as a mechanosensor and therapeutic target. With a comparable loss of function approach we have created a conditional knockout of the coxsackie- and adenovirus receptor to demonstrate that CAR is crucial for embryonic development and determines the electrical properties of the heart. We currently develop CAR inhibitors to affect cardiac remodeling and improve cell based therapies.
Merits of the lab:
The Gotthardt Lab is recognized as a leading research group in the field of muscle biology, particularly for its pioneering work on titin and related proteins. The lab's innovative approach to understanding the molecular basis of muscle diseases has resulted in numerous high-impact publications, making significant contributions to both basic and translational research.
One of the lab’s key merits is its interdisciplinary research methodology, combining molecular biology, genetics, biophysics, and clinical collaboration. This multifaceted approach allows the lab to address complex biological questions and uncover novel insights into muscle function and disease. The use of advanced imaging techniques, state-of-the-art genetic tools, and biophysical measurements further enhances the depth and precision of their research.
The lab’s strong emphasis on collaboration, both within the MDC and with external partners, is another major strength. Through partnerships with clinical departments, hospitals, and international research institutions, the Gotthardt Lab ensures that its research has direct clinical relevance. This collaborative spirit also fosters a dynamic and supportive environment for young scientists and PhD students, providing them with access to cutting-edge resources and expertise.
In addition to its scientific achievements, the Gotthardt Lab is committed to mentoring the next generation of researchers. The lab offers comprehensive training opportunities, emphasizing the development of both technical skills and critical thinking. This dedication to education, combined with the lab’s vibrant research culture, makes it an exceptional place for aspiring scientists to develop their careers.
Why do we train medical doctors in our team?
We train medical doctors in our team to bridge the gap between basic research and clinical practice, fostering collaboration with clinicians, hospitals, and patient networks to translate scientific discoveries into tangible health benefits. Mitch, the group leader is a physician scientist himself.
The position
Meet Liliia!
Biosketch
Liliia obtained her medical degree from Dnipropetrovsk State Medical Academy in Ukraine. In addition to her mandatory coursework, she independently prepared for and successfully passed the United States Medical Licensing Examination (USMLE) Step 1 and Step 2 CK. After graduation in 2019, she worked as a pediatric anesthesiologist in Dnipro, Ukraine. From 2014 to 2021, Liliia dedicated her weekends and vacations to volunteering as a computational neuroscientist at the Bogomoletz Institute of Physiology (Ukraine). Her commitment led to publications in international journals and internships at Aix-Marseille University (France) and Georgia State University (USA). Although computer modeling of neuronal electrical activity was her focus, Liliia had always desired to conduct her own biological experiments. In 2022, she joined the lab of Maria Carmo-Fonseca at Instituto de Medicina Molecular João Lobo Antunes (Portugal) as a research assistant. Liliia utilized iPSC-derived cardiomyocytes as a model to study disease-causing mutations that interfere with cardiac splicing. However, due to the complexity of the interplay between cardiac splicing and cardiovascular disease, many research questions could not be addressed using the cellular model. In March 2023, Liliia started her Ph.D. project in Michael Gotthardt’s lab at the Max- Delbrück Centre for Molecular Medicine, Berlin, Germany, to explore the role of alternative splicing in cardiac health and disease. Liliia is supervised by both Michael Gotthardt and Maria Carmo-Fonseca, who have an ongoing collaboration in a Transatlantic Research Network CASTT (Cardiac Splicing as a Therapeutic Target).
University awarding the PhD
Liliia is currently enrolled in the Charité Universitätsmedizin Berlin.
I decided to become a physician because…
I have never had either an inner calling to become a doctor or a childhood dream of helping people. In school, I was interested in all subjects except sports, which I found primitive – now ironic for me because I developed a passion for regular physical exercises, cycling, and swimming. Having multidisciplinary training, I could choose almost any university, but I entered medical school because of the prospect of lifelong learning. Indeed, medicine was intellectually rewarding and successfully satisfied my permanent thirst for knowledge.
But also, I wanted to become a scientist because…
“When you hear hoofbeats, think horses, not zebras” – this is the central rule clinicians must always keep in mind in their everyday routines. When diagnosing a patient’s symptoms at a hospital, it’s essential to consider common ailments (“horses”) as more probable than rare ones (“zebras”). Clinical work confined my thinking to established algorithms and guidelines for dealing with the “horses.” In contrast, science provided me with the opportunity to create, think exceptionally, ask questions, and take my time exploring the world of “zebras”.
What I am working on?
Titin, the largest protein in the human body, is a fundamental component of the cardiomyocyte contractile machinery, known as the sarcomere. Alternative splicing of titin leads to the expression of two primary isoforms in the heart: N2BA (compliant) and N2B (stiffer). The coexpression of these isoforms at varying levels modulates passive cellular stiffness, thereby influencing cardiac filling. Adjustments of the N2B:N2BA ratio occur during cardiac development and in response to disease. Heart failure with preserved ejection fraction (HFpEF), also called ‘diastolic heart failure’, is characterized by slow and inadequate relaxation in a ventricle with increased stiffness. Finetuning of the ratio between titin isoforms through modulation of cardiac splicing improved diastolic heart dysfunction. However, the molecular mechanisms governing titin-based cellular stiffness adjustment remain poorly understood. In our project, we aim to decipher the splice regulatory networks of titin for healthy and HFpEF hearts as well as align these networks with spatial and functional cardiac modalities. Thus, we will develop and utilize spatial and single-cell full-length sequencing technology to gain insight into the interplay between biomechanics and splicing across cardiac health and disease. Modulation of alternative splicing will enable us to adjust cellular stiffness mediated by titin to improve heart relaxation in HFpEF.
Why is this important to me as a medical doctor?
Heart failure (HF) is a significant global healthcare issue, affecting over 64 million patients worldwide [PMID: 30496104]. Heart failure with preserved ejection fraction (HFpEF), also called ‘diastolic heart failure’, poses one of the most significant challenges of modern medicine. Clinical trials with most of the available cardiovascular therapeutics have failed to meet their primary endpoints. While recent studies have shown improvements in the health status and quality of life among HFpEF patients who were commenced on sodium-glucose cotransporter-2 inhibitor, these positive effects were primarily attributed to a decrease in HF-related hospitalizations rather than a reduction in cardiovascular mortality [PMID: 37622666]. Consequently, there remains an unmet need for the development of innovative, disease-modifying cardiac therapeutics for HFpEF. To address impaired cardiac relaxation, either cellular or interstitial components of cardiac stiffness could be tackled. In our study, we will gain deep insight into titin splice regulatory networks to understand molecular mechanisms governing the adjustment of cardiomyocytic stiffness. Splicing modulators tackling titin-based cellular stiffness could potentially serve as novel therapeutics to improve diastolic cardiac function in HFpEF.
Who am I besides a future physician-scientist?
Besides my beloved motherland Ukraine, two other countries ended up becoming my second home: Portugal and Germany. In Lisbon, I have hiked through the enchanting hills of Sintra and often strolled along the Atlantic Ocean coastline mainly contemplating the beauty of life and science. I have wondered how these peaceful places could have even been created. To truly understand something, the key is to draw it. I captured these picturesque landscapes with oil on canvas as well as filled up a whopping 2GB of my iCloud with photos of Lisbon’s clouds. In Germany, I find inspiration in its classical music heritage, especially through philharmonic concerts renowned for their exceptional acoustics. Baroque compositions hold a special place in my heart. German poems keep my spirit positive and my productivity high. I’ve committed Heinrich Heine’s verses to memory and now delve into the witty works of Christian Morgenstern, Eugen Roth, and Joahim Ringelnatz (kind suggestions of my supervisor ). Life’s a grand adventure, and I’m eager to embrace every chapter. However, one question bothers me: Where will my postdoc lead me, and what new passion will I discover along the way?
