ChemBE Seminar Series: Jan Lemmerding

Description

Jan Lammerding, a professor in the Meinig School of Biomedical Engineering and the Weill Institute for Cell and Molecular Biology at Cornell University, will give a talk titled "Nuclear Mechanobiology: From Metazoan Evolution to New Therapies for Muscle Disease" for the Department of Chemical and Biomolecular Engineering.

Abstract:

Mutations in the LMNA gene, encoding the nuclear envelope (NE) proteins lamins A/C, are responsible for a plethora of human diseases (laminopathies), often specifically affecting striated muscle. The most prevalent laminopathy is LMNA-related dilated cardiomyopathy (LMNA-DCM), with several other laminopathies also exhibiting cardiac defects. The molecular mechanisms leading to the muscle specific pathogenesis remains largely unresolved, presenting a significant challenge in the development of effective therapies. In this keynote talk, I will present our latest (mostly unpublished) studies using multiple mouse models of striated laminopathies, along with cardiac myocytes derived from induced pluripotent stem cells (iPSC-CM) from patients with LMNA mutations. Our findings indicate that LMNA mutations associated with striated muscle disease result in mechanically more fragile nuclei that lead to nuclear envelope rupture in mechanically stressed tissues such as skeletal and cardiac muscle. Intriguingly, disrupting force transmission between the cytoskeleton and nucleus using a dominant negative Linker of Nucleoskeleton and Cytoskeleton complex construct significantly improves survival in two mouse models of LMNA-DCM. Our detailed transcriptomic analysis of multiple human and iPSC-CM models provides further insights into the pathogenic mechanisms underlying striated muscle laminopathies. In parallel, application of precision nuclear run-on sequencing (PRO-seq), a novel technique to detect rapid genome-wide changes in transcription based on mapping active polymerases with base pair resolution, to cells subjected to cyclic biaxial stretch further enabled us to gain an improved understanding into the role of the nucleus and nuclear envelope proteins in the activation of specific genes in response to mechanical stretch. This work was complemented by assessing evolutionary conserved functions of lamins in single cell and metazoan organisms, revealing new insights into the importance of providing nuclear stability in the development of multicellular organisms and new clues into specific lamin functions. Collectively, our work reveals crucial roles of lamin A/C and the nuclear envelope in protecting nuclei from mechanically induced damage and ensuring appropriate mechanoresponses in cells, and offers promising clues into new therapeutic approaches for muscular laminopathies.

Bio:

Jan Lammerding received his diplom ingenieur degree in mechanical engineering from the University of Technology in Aachen, Germany, and completed his PhD in biological engineering at the Massachusetts Institute of Technology, studying subcellular biomechanics and mechanotransduction. Lammerding served as a faculty member at Harvard Medical School/Brigham and Women's Hospital before moving to Cornell University in 2011. The research in the Lammerding Laboratory is focused on nuclear mechanobiology, investigating how the mechanical properties of the nucleus modulate cellular functions, and how physical forces acting on the nucleus affect its structure and processes. The multidisciplinary research approach combines the development of novel experimental assays with cell and molecular biology techniques and in vivo models. Lammerding has published over 100 peer-reviewed articles, including in Nature, Science, and PNAS.

Lammerding is a fellow of the American Society for Cell Biology, the Biomedical Engineering Society, and the American Institute for Medical and Biological Engineering. His research is supported by awards from the National Institutes of Health, the National Science Foundation, and the Volkswagen Foundation. Learn information about the research in the Lammerding lab.