Craig Wheelock

Craig Wheelock

Principal Researcher | Docent
Visiting address: Nobels väg 13, 17177 Stockholm
Postal address: C6 Institutet för miljömedicin, C6 Integrativ metabolomik Wheelock, 171 77 Stockholm
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Grants

  • Swiss National Science Foundation
    1 January 2023 - 31 December 2026
    Helminths are multicellular parasites with potent regulatory effects on immune responses in infection and inflammation. We have recently identified an immune regulatory protein of the helminth Heligmosomoides polygyrus bakeri (Hpb), glutamate dehydrogenase (GDH), which modulates macrophage activation and allergic airway inflammation when administered in a murine asthma model. Here, we aim to characterize the mechanisms of action and immune regulatory effects of Hpb GDH in models of infection and vaccination. In part A of the project, we intent to identify the cellular interaction partners of Hpb GDH by co-immunoprecipitation and pull-down experiments using Strep-tagged Hpb GDH followed by mass spectrometry-based proteomics. By determining the structure of Hpb GDH and its identified interaction partners using X-ray crystallography and cryo-EM, we aim to gain further insights into the structural particularities of Hpb GDH compared to its mammalian homologues and into the molecular interactions with its cellular targets. Based on our recent findings, suggesting histone 3 lysine 27 acetylation (H3K27ac) as a mechanism mediating the Hpb GDH-driven modulation of macrophage gene expression, we will perform ChIP sequencing to identify loci that are epigenetically targeted by Hpb GDH. These structural and mechanistic insights will be instrumental for further developing Hpb GDH as a new biotherapeutic against airway disease.In part B of the project, we aim to identify the relevance of Hpb GDH-driven cytokine production for the protein’s effects on host defense and vaccine responses. Our RNA sequencing data indicate that Hpb GDH induces a strong type I interferon (IFN) and IL-12 cytokine signature. We will study effects of Hpb GDH in mice lacking IFN signaling in the hematopoietic or myeloid compartment (Ifnar fl/fl x Vav1Cre/ Lyz2Cre/ Cx3cr1Cre) or with global deficiencies in IL-12 family members (Il12b-/-, Ebi3-/-) in established mouse models of helminth infection. Effects of Hpb GDH on vaccination efficacy against major human pathogens as well as roles of IL-12 family cytokines in the regulation of vaccine-induced T-cell responses will be elucidated in mouse models of BCG and influenza vaccination.In summary, our work will contribute to a better understanding of the regulation of host defense, inflammation and vaccine responses by helminth molecules. The proposed studies may foster the translation of Hpb GDH into a novel biotherapeutic for the treatment of infectious and inflammatory diseases.
  • Swedish Research Council
    1 January 2023 - 31 December 2026
    Asthma ranks among the most common chronic diseases of industrialized countries. Upwards of 20% of asthmatics present with difficult to control conditions that often respond poorly to current therapies, creating a significant unmet need to optimize individual patient treatment. Asthma is a general term used for a broad spectrum of loosely defined clinical conditions for which there is no defined biochemical description. Metabolomics provides a real-time indicator of biological status, reflecting the integrated result of genetic and environmental interactions, as well as treatment responses, making it ideally suited for molecular characterization of asthma. This project will use metabolomics to identify molecular phenotypes of severe airway disease. We will perform the largest meta-analysis of metabolomics to date consisting of tens-of-thousands of individuals, which will be complemented with metabolomics and lipid mediator analysis of treatment interventional studies. These data will be integrated using novel bioinformatics approaches to identify key metabolites that discriminate phenotypes and treatable endotypes. This information will be used to develop a targeted assay for asthma molecular phenotyping. The assay will be tested in validation cohorts to determine accuracy in stratifying individuals for treatment. The development of a high-throughput targeted molecular phenotyping panel will enable clinical translation and actualize precision medicine treatment for asthma.
  • Swedish Research Council
    1 January 2022 - 31 December 2025
    Biological mass spectrometry (BioMS) is based on volatilization and ionization of compounds of interest and measuring their mass-to-charge ratios. In order to derive structural information, the gas-phase ions are dissociated in tandem mass spectrometry (MS/MS) into fragments by collisions with neutrals, electrons or photons. The process of ion activation and dissociation of fundamental importance in MS/MS, and it has traditionally been focused on large molecules. The recent emergence of single-cell proteomics and metabolomics requires refocusing the MS/MS development efforts to smaller molecules, such as peptides and lipids, for which extreme sensitivity is required. Here we envision a new MS/MS platform (Post-Ionization and Fragmentation of Gas-phase ions for Single Organism Analysis, PIFAGOR) for proteomics and metabolomics of single cells and small organisms, such as C. Elegans, a popular model organism in Molecular biology. In PIFAGOR, the ionic charge state of precursor ions will be increased by electron impact concomitantly with dissociation. The total charge of ionic fragments in such electron ionization dissociation  (EID) MS/MS will be larger than the original charge of the precursor ions, thus achieving ≥100% fragmentation efficiency. Also, novel liquid phase separation online with new fragmentation methods such as Coulomb explosion will be implemented. Achieving this would be a fundamental accomplishment for BioMS and its applications in biomedical sciences.
  • Swedish Research Council
    1 December 2021 - 30 November 2025
    Since the inception of the SARS-CoV-2 pandemic, the focus of authorities and healthcare providers has been on reducing the mortality acute, severe form of COVID-19. While the mortality rate of individuals affected by severe COVID-19 has been relatively high, they have made up a small proportion of those infected. A much larger group of severely affected individuals has instead emerged: those with persistent disease. It is important to highlight that the majority of long-COVID patients do not consist of individuals with prolonged recovery after hospitalization, but instead constitute a completely different phenotype of the disease, in a different demographic group. While those requiring hospital care are largely elderly or multi-morbid individuals, the majority of long-COVID patients are formerly young, mentally and physically strong individuals who due to mild initial symptoms generally did not seek hospital care. Here we will develop a home monitoring system to facilitate continuous follow-up of long-COVID patients. Identification of daily fluctuations, activity and physiological parameters will help identify sub-groups of the disease, with specific emphasis on those with lung involvement. Associated molecular biomarkers will be evaluated using our systems medicine workflow both in lung samples collected with bronchoscopy, and in a non-invasive fashion using PExA. The fully developed system will also be used to evaluate the effectiveness of various forms of treatment.
  • Swedish Heart-Lung Foundation
    1 January 2021 - 31 December 2023
  • Swedish Research Council
    1 January 2021 - 31 December 2024
  • Swedish Heart-Lung Foundation
    1 January 2021 - 31 December 2021
  • Swedish Heart-Lung Foundation
    1 January 2019 - 31 December 2021
  • Swedish Heart-Lung Foundation
    1 January 2019 - 31 December 2021
  • Swedish Research Council
    1 January 2017 - 31 December 2020
  • Clinical biomarkers for ROS-based anticancer therapy
    Swedish Foundation for Strategic Research
    1 January 2015 - 31 December 2019
  • An integrative systems biology approach to understanding inflammatory neurological diseases.
    Canadian Institutes of Health Research
    1 April 2014 - 30 June 2016

Employments

  • Principal Researcher, Institute of Environmental Medicine, Karolinska Institutet, 2022-

Degrees and Education

  • Docent, Karolinska Institutet, 2009

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