Research Focus Teams
COVID-19, Rare Diseases, Cancer, Diabetes
Research Interests
Bone Remodeling, Cancer, Cardiovascular Regeneration, Immunopathology, Neurodegenerative Diseases->
Departments
Medical Genetics
Bio
Dr. Josef Penninger is a Canada 150 Chair in Functional Genetics, Allen Distinguished Investigator, and served as the Director of the Life Sciences Institute at the University of British Columbia, December 2018 - 2023. Prior to this, from 2002-2018, he was the Scientific and Founding Director of IMBA, the Institute for Molecular Biotechnology of the Austrian Academy of Sciences, in Vienna, Austria. From 1994-2002, he worked as a lead researcher at the Amgen Research Institute in Toronto, affiliated with the University of Toronto and the Ontario Cancer Research Center.
Research Summary
Our goal is to develop new and effective treatments for diseases by uncovering the fundamental biological principles underlying development and disease. 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 diseases.
Although our research falls under four 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.
Ongoing Projects
Blood vessel engineering -
The prevalence of diabetes is increasing constantly, resulting in a global epidemic. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke or lower limb amputation; in large parts because of marked changes in blood vessels, defined by expansion of the basement membrane and a loss of vascular cells. Diabetes also impairs endothelial cell (EC) function and disturbs EC-pericyte communication. How endothelial/pericyte dysfunction leads to diabetic vasculopathy remains largely elusive. Here we report the development of self-organizing 3D human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks enveloped by a basement membrane. Human blood vessel organoids transplanted into mice form a stable, perfused vascular tree, including arteries, arterioles and venules. Exposure of blood vessel organoids to hyperglycemia and inflammatory cytokines in vitro induced thickening of the vascular basement membrane. Human blood vessels, exposed in vivo to a diabetic milieu in mice, also mimic the microvascular changes in diabetic patients. Dll4-Notch3 were identified as key drivers of diabetic vasculopathy in human blood vessels. Thus, organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable to model and identify regulators of diabetic vasculopathy, affecting hundreds of millions of patients. (Wimmer et al. Nature 2019)
BH4 -
Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in monoamine neurotransmitter production, nitric oxide generation and pain. We now identify a fundamental role for BH4 in T cell biology. Genetic inactivation of GTP cyclohydrolase 1 (GCH1), the rate-limiting enzyme in the synthesis of BH4 and inhibition of sepiapterin reductase (SPR), the terminal enzyme in its synthetic pathway, severely impair the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. In vivo blockade of BH4 synthesis abrogates T cell-mediated autoimmunity and allergic inflammation, while enhancing BH4 levels by GCH1 overexpression, augments CD4+ and CD8+ T cell responses increasing their anti-tumour activity in vivo. Administration of BH4 to mice markedly reduces tumour growth and expands intra-tumoral effector T cells. Kynurenine, a tryptophan metabolite that blocks anti-tumour immunity, inhibits T cell proliferation in a manner that can be rescued by BH4. Finally, developed a potent SPR antagonist for potential clinical use. Our data uncover GCH1, SPR and their downstream metabolite BH4, as critical regulators of T cell biology, which can be readily manipulated to either block autoimmunity or enhance anti-cancer immunity. For me as trained T cell biologist, who wrote the first CTLA4 knock-out paper, it's quite amazing to find an entirely unexpected new pathway required for T cell biology - blocking the pathway we can control e.g. multiple autoimmune diseases or allergic airway inflammation. (Cronin et al. Nature 2018).
Glycoproteomics in cancer -
Glycosylation, the covalent attachment of carbohydrate structures onto proteins, is the most abundant post-translational modification. Over 50% of human proteins are glycosylated, which alters their activities in diverse fundamental biological processes. Despite its importance in biology, the identification and functional validation of complex glycoproteins has remained largely unexplored. We developed a novel quantitative approach to identify intact glycopeptides from comparative proteomic data-sets, allowing us to not only infer complex glycan structures but also to directly map them to sites within the associated proteins at the proteome scale. We applied this method to human and murine embryonic stem cells to illuminate the stem cell glycoproteome. This analysis nearly doubles the number of experimentally confirmed glycoproteins, identifies previously unknown glycosylation sites and multiple glycosylated stemness factors, and uncovers evolutionarily conserved as well as species-specific glycoproteins in embryonic stem cells. The specificity of our method was confirmed using sister stem cells carrying repairable mutations in enzymes required for fucosylation, Fut9 and Slc35c1. Ablation of fucosylation confers resistance to the bioweapon ricin, and we discovered proteins that carry a fucosylation-dependent sugar code for ricin toxicity. Mutations disrupting a subset of these proteins rendered cells ricin resistant, revealing new players that orchestrate ricin toxicity. Our novel comparative glycoproteomics platform enables genome-wide insights into protein glycosylation and glycan modifications in complex biological systems. (Stadlmann et al. Nature 2017).
Haploid stem cells -
The ability to directly uncover the contributions of genes to a given phenotype is fundamental for biology research. However, ostensibly homogeneous cell populations exhibit large clonal variance that can confound analyses and undermine reproducibility. We used genome-saturated mutagenesis to create a biobank of over 100,000 individual haploid murine embryonic stem cell (mESC) lines targeting 16,950 genes with genetically bar-coded, conditional and reversible mutations. This Haplobank is the largest resource of hemi-/homozygous mutant mESCs to date and is available to all researchers. Reversible mutagenesis overcomes clonal variance by permitting functional annotation of the genome directly in sister cells. We utilize Haplobank in reverse genetic screens to investigate the temporal resolution of essential genes in mESCs, and to identify novel genes that control sprouting angiogenesis and blood vessel lineage specification. Further, a genome-wide forward screen with Haplobank identified PLA2G16 as a host factor required for cytotoxicity by rhinoviruses, which cause the common cold. Thus, Haplobank clones and revertible technologies enable high-throughput, reproducible functional annotation of the genome. (Elling et al. Nature 2017).
Collaborations:
Clifford Woolf, Harvard Medical School - BH4
Hudson Freeze, San Diego - Glycoproteomics
Juergen Knoblich, IMBA, Vienna - tissue engineering
Jingson Li, Chinese Academy of Sciences - haploid stem cells
Recent Publications
Bat organoids reveal antiviral responses at epithelial surfaces
Nicotinamide modulates gut microbial metabolic potential and accelerates recovery in mild-to-moderate COVID-19
Metabolic mapping of the human solute carrier superfamily
Fate and state transitions during human blood vessel organoid development
Identification of a protective antigen reveals the trade-off between iron acquisition and antigen exposure in a global fungal pathogen
RANK drives structured intestinal epithelial expansion during pregnancy
Non-targeted N-glycome profiling reveals multiple layers of organ-specific diversity in mice
Murine neonatal cardiac regeneration depends on Insulin-like growth factor 1 receptor signaling.
Mast cell-derived BH4 and serotonin are critical mediators of postoperative pain.
Engineering next generation vascularized organoids.
Synchronized development of thymic eosinophils and thymocytes
Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19
Crimean-Congo haemorrhagic fever virus uses LDLR to bind and enter host cells
Apelin regulates skeletal muscle adaptation to exercise in a high intensity interval training (HIIT) model
Generation of complex bone marrow organoids from human induced pluripotent stem cells
A microfluidic platform integrating functional vascularized organoids-on-chip
Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism
RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes
Identification of CCZ1 as an essential lysosomal trafficking regulator in Marburg and Ebola virus infections
Sequential multi-omics analysis identifies clinical phenotypes and predictive biomarkers for long COVID
The HACE1 E3 ligase mediates RAC1-dependent control of mTOR signaling complexes
Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern
FAM3C/ILEI protein is elevated in psoriatic lesions and triggers psoriasiform hyperproliferation in mice
Apoptotic cell death in disease-Current understanding of the NCCD 2023
Low-density lipoprotein receptor-related protein 1 (LRP1) as an auxiliary host factor for RNA viruses
PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing
Blood Vessel Organoids for Development and Disease
A whole-genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors
Angiotensin-converting enzyme 2-at the heart of the COVID-19 pandemic
Apelin expression is downregulated in T cells in a murine model of chronic colitis
Generation of Human Blood Vessel Organoids from Pluripotent Stem Cells
Cardiac regeneration: Options for repairing the injured heart
Electric field stimulation boosts neuronal differentiation of neural stem cells for spinal cord injury treatment via PI3K/Akt/GSK-3β/β-catenin activation
Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level
Protocol for SARS-CoV-2 infection of kidney organoids derived from human pluripotent stem cells
RANKL and RANK in Cancer Therapy
Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models
The HUSH complex controls brain architecture and protocadherin fidelity
A molecularly engineered, broad-spectrum anti-coronavirus lectin inhibits SARS-CoV-2 and MERS-CoV infection in vivo
The impact of heme biosynthesis regulation on glioma aggressiveness: Correlations with diagnostic molecular markers
Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer
AIF Overexpression Aggravates Oxidative Stress in Neonatal Male Mice After Hypoxia-Ischemia Injury
Pulmonary Surfactant Proteins are Inhibited by IgA Autoantibodies in Severe COVID-19
FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder
ACE2-like enzyme B38-CAP suppresses abdominal sepsis and severe acute lung injury
Targeting Glycans for CAR Therapy: the Advent of Sweet CARs
Development of an aerosol intervention for COVID-19 disease: Tolerability of soluble ACE2 (APN01) administered via nebulizer
Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants
Neuropeptide Neuromedin B does not alter body weight and glucose homeostasis nor does it act as an insulin-releasing peptide
Contact-dependent signaling triggers tumor-like proliferation of CCM3 knockout endothelial cells in co-culture with wild-type cells
Evidence in favor of the essentiality of human cell membrane-bound ACE2 and against soluble ACE2 for SARS-CoV-2 infectivity
Redirecting Imipramine against Bluetongue Virus Infection: Insights from a Genome-wide Haploid Screening Study
A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells
Recalibrating vascular malformations and mechanotransduction by pharmacological intervention
Adult T-cells impair neonatal cardiac regeneration
TSPAN6 is a suppressor of Ras-driven cancer
Transcription factor Mesenchyme Homeobox Protein 2 (MEOX2) modulates nociceptor function
ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology
Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19
Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor