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Welcome to the Penninger Lab

Somewhere, something incredible is waiting to be known.” (Carl Sagan) - I think this quote epitomizes the essence of science - the unpredictability of research and the excitement of discovery.

Diseases can no longer be pigeon-holed into distinct anatomical regions. For instance, we now know that Parkinson’s disease is not simply a neurological condition but rather involves many additional players such as our immune system, blood system and even the microflora in our gut. Similarly, our lab has shown for example how one factor, RANKL, is important in a variety of biological processes and diseases from bone metabolism to immune functioning to thermoregulation to breast and lung cancers. Using a holistic approach to understand the role each system plays in a disease and also how the same gene can affect many physiological processes is essential to develop new and effective treatments. We are not afraid to wander off the beaten track and merge ideas from apparently disparate fields.    

Aims

Our goal is to develop new and effective treatments for various diseases by uncovering the fundamental biological principles underlying development and disease.

Approach

Our lab is full of highly motivated and creative scientists. Together we wish to understand the architecture and underlying mechanisms of human disease, with the ultimate aim of identifying novel therapeutic strategies.

To accomplish our goals, we develop and deploy a broad range of in vitro and in vivo tools that reveal the fundamental mechanisms involved in human disease. These approaches include genetic editing in vitro and in vivo, human induced pluripotent cell (iPS cell) models of disease, haploid cells for genetic as well as compound screening paradigms, mouse and human organoid cultures, as well as genetically engineered mice. Our multidisciplinary techniques enable us to model and study the complexity of human diseases.

Although our research falls under five broadly defined thematic areas below, these systems are subject to substantial crosstalk. As a result, our research in one field influences and informs another, leading to unexpected insight and advances that acknowledge and embrace the complexity of disease and biology.

BoneWe are interested in the dynamic nature of bone remodeling, and how the delicate equilibrium of bone production and bone absorption is disrupted not only under pathological conditions but also during the normal ageing process.

BrainAs we are now living longer than ever before, it is becoming increasingly more relevant to uncover, and treat, the underlying mechanisms driving neurodegenerative diseases such as Parkinson’s and Alzheimer’s, as well as chronic neurological conditions such as motor neuron disease and neuropathic pain. In the lab, we use brain organoids, iPS-derived neuronal cultures and neurodegenerative modeling to reveal and address key aspects of these debilitating diseases.

Cancer 14.1 million new cases of cancer are diagnosed each year worldwide, and this figure is expected to rise by 70% over the next two decades! In the lab, we are determined to combat this relentless disease. Using various genetic, orthotopic as well as hormonally- and chemically-induced mouse models of breast, lung, colon, and pancreatic cancers combined with datasets from various human cancers, we aim to explore novel genes and pathways involved in cancer initiation, growth and metastasis. In particular, we have made great strides in understanding how hormones regulate a crucial signaling pathway to drive stochastic and inherited breast cancers. We will use this knowledge to understand and, ultimately, help cure or prevent cancer.

Cardiovascular –  According to the World Health Organisation (WHO), cardiovascular diseases are the number one killer worldwide, causing 1000 deaths/hour on average. In our lab, we seek to unravel mechanisms that allow the heart to regenerate after severe myocardial infarction. Furthermore, we have established an efficient blood vessel differentiation assay to screen a collection of 100,000 individual haploid murine embryonic stem cell lines (HaploBank) targeting 16,950 genes for new targets of blood vessel growth. Insights from this research will be invaluable for treating dysfunctional blood vessel regulation observed in ischemic diseases, cancer and diabetic retinopathies.

Immunity –  Our lab has a long-standing passion to understand how the immune system copes with the amazing array of pathogens in our environment. Previously, we have researched many facets of the immune system, from developmental immunology to pathological conditions of the immune system. For instance, we have investigated autoimmunity, paying particular attention to the important role of T cells in autoimmune diseases and in cancer immunotherapy. Recently, we have also studied the role of the innate immune system in protecting the host against fungal infections, a serious health issue which claims the lives of 1.5 million people per year.

Impact

We take a holistic approach to understanding health and disease. We use or develop novel approaches to answer complex biological questions. Our research will advance our knowledge of biology, reveal mechanisms that prevent or drive disease, and provide opportunities to design new treatment strategies. 

Selected Publications

Wirnsberger, G., Zwolanek, F., Asaoka, T., Kozieradzki, I., Tortola, L., Wimmer, RA., Kavirayani, A., Fresser, F., Baier, G., Langdon, WY., Ikeda, F., Kuchler, K., Penninger, JM. (2016). Inhibition of CBLB protects from lethal Candida albicans sepsis. Nat Med. 22(8):915-23

Sigl, V., Owusu-Boaitey, K., Joshi, PA., Kavirayani, A., Wirnsberger, G., Novatchkova, M., Kozieradzki, I., Schramek, D., Edokobi, N., Hersl, J., Sampson, A., Odai-Afotey, A., Lazaro, C., Gonzalez-Suarez, E., Pujana, MA., Cimba, F., Heyn, H., Vidal, E., Cruickshank, J., Berman, H., Sarao, R., Ticevic, M., Uribesalgo, I., Tortola, L., Rao, S., Tan, Y., Pfeiler, G., Lee, EY., Bago-Horvath, Z., Kenner, L., Popper, H., Singer, C., Khokha, R., Jones, LP., Penninger, JM. (2016). RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res. 26(7):761-74

Paolino, M., Choidas, A., Wallner, S., Pranjic, B., Uribesalgo, I., Loeser, S., Jamieson, AM., Langdon, WY., Ikeda, F., Fededa, JP., Cronin, SJ., Nitsch, R., Schultz-Fademrecht, C., Eickhoff, J., Menninger, S., Unger, A., Torka, R., Gruber, T., Hinterleitner, R., Baier, G., Wolf, D., Ullrich, A., Klebl, BM., Penninger, JM. (2014). The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 507(7493):508-12

Hanada, T., Weitzer, S., Mair, B., Bernreuther, C., Wainger, BJ., Ichida, J., Hanada, R., Orthofer, M., Cronin, SJ., Komnenovic, V., Minis, A., Sato, F., Mimata, H., Yoshimura, A., Tamir, I., Rainer, J., Kofler, R., Yaron, A., Eggan, KC., Woolf, CJ., Glatzel, M., Herbst, R., Martinez, J., Penninger, JM. (2013). CLP1 links tRNA metabolism to progressive motor-neuron loss. Nature. 495(7442):474-80

Hashimoto, T., Perlot, T., Rehman, A., Trichereau, J., Ishiguro, H., Paolino, M., Sigl, V., Hanada, T., Hanada, R., Lipinski, S., Wild, B., Camargo, SM., Singer, D., Richter, A., Kuba, K., Fukamizu, A., Schreiber, S., Clevers, H., Verrey, F., Rosenstiel, P., Penninger, JM. (2012). ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 487(7408):477-81

Elling, U., Taubenschmid, J., Wirnsberger, G., O'Malley, R., Demers, SP., Vanhaelen, Q., Shukalyuk, AI., Schmauss, G., Schramek, D., Schnuetgen, F., von Melchner, H., Ecker, JR., Stanford, WL., Zuber, J., Stark, A., Penninger, JM. (2011). Forward and reverse genetics through derivation of haploid mouse embryonic stem cells. Cell Stem Cell. 9(6):563-74

Schramek, D., Leibbrandt, A., Sigl, V., Kenner, L., Pospisilik, JA., Lee, HJ., Hanada, R., Joshi, PA., Aliprantis, A., Glimcher, L., Pasparakis, M., Khokha, R., Ormandy, CJ., Widschwendter, M., Schett, G., Penninger, JM. (2010). Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. 468(7320):98-102

Funding