The LEO Foundation Award 2018 – Silver Award

Grantee: Dr. Tiffany Scharschmidt

Amount: DKK 500,000

Grant category: LEO Foundation Awards

Year: 2018

Geography: USA

The Silver Award went to Dr. Tiffany Scharschmidt from University of California San Francisco, USA, for her work on the skin microbiome and its interplay with the adaptie immune system.

Have a sneak peek into her research Video about Dr. Tiffany Scharschmidt

Fully Synthetic Lincosamides to Combat Multidrug-Resistant Skin Infections

Grantee: Prof. Dr. Andrew G. Myers, Amory Houghton Professor of Chemistry Harvard University, Cambridge, MA

Amount: DKK 3,108,110

Grant category: Research grants in open competition

Year: 2018

Geography: USA

Many common skin infections are caused by the Gram-positive bacterial species Staphylococcus aureus and Streptococcus pyogenes. The infections lead to conditions ranging in severity from minor folliculitis to life threatening skin reactions. If not managed successfully, they may escalate into lethal systemic infections.

Commonly, these diseases are treated with clindamycin, a prototypical member of the wide-ranging so-called lincosamide antibiotic class. Its clinical importance is underlined by the World Health Organization’s listing of it as an essential medicine. In the past decades, however, prevalence of in particular lincosamide resistant Staphylococci and Streptococci has risen sharply. The rise threatens to diminish clindamycin’s usability in the future, even render it obsolete.

In the course of this project, the team led by Andrew G. Myers of Havard University, will seek to address this growing unmet medical need by synthetic discovery efforts focused on the lincosamide class.

The team’s preliminary results indicate that new lincosamides uncovered in this fashion are able to address the contemporary resistance threats: Many of the compounds designed, synthesised, and evaluated by the team to date have shown themselves active against multidrug-resistant clinical isolates of Staphylococci and Streptococci, and at the same time they demonstrate favourable pharmacokinetic and safety profiles.

The team expects that it can uncover new candidates displaying expanded spectra of action against MDR and Gram-negative bacteria. The expected results can then be used to advance refined lead candidates capable of demonstrating efficacy in in vivo murine models of skin infection, and thus yield substantial promise for further clinical development of actual treatments.

 

Project group

Dr. Amarnath Pisipati, Postdoctoral microbiologist

Matthew J. Mitcheltree, PhD student, chemistry

Ioana Moga, PhD student, chemistry

Katherine J. Silvestre, PhD student, chemistry

 

International affiliation

The Institut Pasteur, Annecy, France – International Course on Antibiotics and Resistance (ICARe), Organizing Committee, Core Faculty

In vivo model of human melanoma using a novel crest chimera system

Grantee: Dr. Rudolf Jaenisch, Member, Whitehead Institute and Professor, Department of Biology, Massachusetts Institute of Technology, MA

Amount: DKK 2,476,836

Grant category: Research grants in open competition

Year: 2018

Geography: USA

Two major challenges when using mouse models to model human cancers such as melanoma are that the human tumor cells transplanted to mice 1) represent the end-stage of the disease and 2) that the host animals are usually immunocompromised.

Thus, these models fail to actually show development of the disease and they fail to display the ongoing interaction between melanoma cells and the immune system as the disease progresses.

To curb these two shortcomings, the team led by Rudolf Jaenisch of Massachusetts Institute of Technology, has set out to create an experimental model system that will make it possible to study initiation, progression, and manifestation of human melanoma in immune competent host animals.

Their basis is generation of human-mouse neural crest chimeras – where mice embryos are introduced with human neural crest cells carrying the genetic dispositions alleged to lead to development of the particular cancer – and their goal is a model that has the potential to show how melanoma cells evade the immune system.

Given a positive outcome, this innovative project can help devise strategies to improve the effectiveness of current immunotherapies, to test novel immunotherapies, and to identify novel targets in melanoma treatment.

 

Project group

Malkiel Cohen, Postdoctoral researcher

Kristin Andrykovich, Graduate Assistant

Probing the function of melanosomal transporters in pigmentation using metabolic profiling

Grantee: David M. Sabatini, Whitehead Institute of Biomedical Research

Amount: DKK 1,278,270

Grant category: Research grants in open competition

Year: 2018

Geography: USA

Studies in human populations have identified dozens of pigmentation genes, many of which encode proteins with well-understood functions, such as in melanocyte development, melanin biosynthesis, and the biogenesis and trafficking of specialized melanin-containing organelles called melanosomes.

Yet, there are other pigmentation genes that we know much less about, such as those that encode putative transporter proteins on the melanosome surface. These putative melanosomal transporters have been reported to import precursor metabolites for melanin synthesis or regulate melanosomal pH; however, many of these findings have been controversial or speculative. Deciphering the molecular function of these putative transporters and their physiological substrates is crucial to our understanding of pigmentation.

To address this problem, we propose to determine the metabolite composition of melanosomes and define the role of individual transporters in melanosomal function. We will develop a purification method to rapidly isolate intact melanosomes and analyse them by liquid chromatography and mass spectrometry to compile the first catalog of melanosomal metabolites. We will subsequently characterize SLC45A2, a putative melanosomal transporter that modulates human pigmentation in response to sunlight. By comparing the metabolite profile of wild-type versus SLC45A2-deficient melanosomes, we will identify candidate SLC45A2 substrates and validate them using biochemical assays, a workflow that will be applied to other putative melanosomal transporters.

This study will present the first detailed analysis of melanosome metabolites, as well as identify key metabolites and their transporters essential for melanogenesis. This work could inform new ways to modulate pigmentation and treat pigmentation pathologies.

Nucleic Acid Ionic Liquids (NAILs) for Topical Skin Applications

Grantee: Samir Mitragotri, Harvard John A. Paulson School of Engineering and Applied Sciences

Amount: DKK 2,000,043

Grant category: Research grants in open competition

Year: 2018

Geography: USA

We will develop a novel ionic-liquid formulation for topical delivery of nucleic acids into the skin.

Our ionic liquid enhances lipophilicity of nucleic acids by ~100,000,000 fold and enhances their penetration into the skin. We will demonstrate the feasibility of the platform through delivery and efficacy of two siRNAs. The resulting platform is expected to have broad applications to other nucleic acid drugs including mRNA for the treatment of a wide range of dermatological conditions.

Our ionic liquid platform will open new opportunities for the treatment of dermatological conditions.

Endosomal Chemokine Receptor Signaling as Basis for Metastasis in Malignant Melanoma

Grantee: Alex Rojas Bie Thomsen, Columbia University Medical Center

Amount: DKK 3,600,308

Grant category: Research grants in open competition

Year: 2018

Geography: USA

Melanoma is the deadliest form of skin cancer with few treatment options to patients with advanced metastatic disease.

Melanoma metastasis to lymph nodes is associated with expression of the chemokine receptor CCR7, a member of the G protein-coupled receptors (GPCRs) superfamily that promote cell migration of immune cells. Classically, upon agonist stimulation, GPCRs at the cell membrane activate heterotrimeric G proteins, causing downstream signaling throughout the cell. In order to terminate G protein signaling, cells have devised a specialized desensitization mechanism that includes receptor phosphorylation by GPCR kinases and subsequent recruitment of β-arrestins (βarrs) to the phosphorylated receptors. The GPCR–βarrs interaction both blocks the G proteinbinding site and promotes receptor endocytosis.

However, we recently discovered that some GPCRs interact with G proteins and βarrs simultaneously to form GPCR–G protein–βarr ‘megaplexes’, which allows the receptor to continue to stimulate G protein signaling while being internalized into endosomes by βarrs. Our preliminary results suggest that CCR7 forms megaplexes and promotes G protein signaling from internalized compartments. Interestingly, endosomal signaling, in general, is highly involved in cell migration, and different proteins are trafficked between plasma membrane and endosomes during this process. Thus, the proposed project aims to investigate the involvement of endosomal CCR7 signaling in melanoma cell migration. Furthermore, using a combination of highly advanced cryo-electron tomography and APEX2 proteomics, we will visualize the mechanism of CCR7-mediated melanoma cell migration protein-by-protein. Such detailed mechanistic knowledge will assist in designing innovative therapeutics to treat metastatic malignant melanoma.

Developing a Cell-Based Therapy for Alopecia

Grantee: George Cotsarelis, Perelman School of Medicine, University of Pennsylvania, Philadelphia

Amount: DKK 3,793,808

Grant category: Research grants in open competition

Year: 2018

Geography: USA

Androgenetic alopecia (AGA, Male or Female Pattern Baldness) is the most common type of hair loss, affecting approximately 50% of men and 30% of women by the age of 50.

Current therapies, including pharmaceutical and surgical interventions, are either marginally effective or expensive with significant limitations. Over the last decade, breakthroughs made in the field of adult stem cells have laid the foundation for a cell-based approach to tissue and organ regeneration. Cell-based therapies will comprise a new wave of medical breakthroughs.

In this study we propose to produce human hair follicles from induced pluripotent stem (iPS) cells by directing these cells to form the two types of cells that are needed for human hair formation, namely the human hair follicle epidermal cells and the hair inductive dermal fibroblasts.

We will combine our hair biology and tissue-engineering expertise to generate early stage human hair follicles in culture that can be implanted into an animal model to grow into a mature hair. The long-term goals are to develop an innovative cell-based treatment for hair loss and an in vitro platform for testing hair growth compounds.

The 2019 Gordon Research Conference on Epithelial Differentiation and Keratinization (GRC-EDK)

Grantee: Valentina Greco, Yale University, New Haven, Connecticut

Amount: DKK 146,536

Grant category: Education and awareness grants

Year: 2018

Geography: USA

The 2019 Gordon Research Conference on Epithelial Differentiation and Keratinization (GRC-EDK) is the premier international meeting in epithelial biology since 1979. It showcases the latest conceptual and technological advances in epithelial biology bridging basic and translational research.

This 2019 meeting entitled “Innovations in basic and translational epithelial biology” aims to bring together preeminent speakers at the forefront of epithelia development, stem cell biology, cell biology, pathology and therapy.

The main objective is to discuss latest developments and generate synergistic approaches towards future discoveries and therapeutic prospects. To ensure this, over 30% of speakers are from outside the immediate field, 50% did not speak in the 2017 meeting, and over 30% will be selected from submitted abstracts. Finally, a power hour will open a debate on ways to recognize and tackle discriminations in science.

Trainee mentorship will be promoted through the 4th Gordon Research Seminar on Epithelial Differentiation and Keratinization (GRS-EDK), immediately preceding the GRC-EDK. GRS meetings are organized and featured by trainee scientists providing a unique opportunity to discuss their research and develop life-long collaborations.

The GRS-EDK will also feature a career mentoring panel discussion with emphases on transitioning to independence, careers in academia versus industry, and the importance of gender and racial diversity within science. Collectively, this GRC/GRS will move forward cutting-edge research in the area of skin biology, promote translation of key research findings to clinical practice, and further the careers of early stage investigators to maintain the highest level of innovation of this field in the future.

Investigating the tumor suppressive functions of Notch signaling during skin cancer initiation and progression

Grantee: Sunny Y. Wong, Assistant Professor, University of Michigan, Ann Arbor

Amount: DKK 2,486,354

Grant category: Research grants in open competition

Year: 2018

Geography: USA

Basal cell carcinoma (BCC) is the world’s most common cancer and is defined by uncontrolled activation of the Hedgehog (Hh) signaling pathway.

Although previous studies have suggested that elevated Hh may be sufficient for BCC formation, mutations in the Notch pathway are also commonly observed. Furthermore, Notch-deficient mice are susceptible to forming BCCs, and our recent studies have shown that Notch can modulate tumor-drug response.

These studies seek to understand whether Notch affects multiple aspects of BCC tumorigenesis. Using a combination of animal studies and human BCC specimens, we will investigate how Notch modulates tumor progression and stem cell origin.

We will also model in mice a recent clinical trial, where Alzheimer’s patients treated with a Notch inhibitor reported increased incidence of BCC. We hypothesize that Notch may suppress tumorigenesis at multiple levels by controlling cell differentiation, apoptosis and turnover, similar to its function in normal skin and hair follicles.

These studies will ultimately build on the novel premise that BCCs may originate from a precursor lesion. Given that Notch mutations are the most commonly observed genetic aberrations in human skin, a deeper understanding of the tumor suppressive properties of this pathway is urgently needed.

Compartmentalized and Systemic Interactions of the Skin Microbiome in Cancer Immunotherapy Response

Grantee: Julia Oh, Jackson Laboratory, Farmington, Connecticut

Amount: DKK 2,107,529

Grant category: Research grants in open competition

Year: 2018

Geography: USA

My vision is to use metagenomics to better predict patient responses to immunotherapy and rationally design microbial adjuvant cocktails and engineered microbes to improve therapeutic outcomes.

However, a central question is the role of the local microbiota vs. systemic effects in potentiating these immunotherapeutics. In skin cancer, we have been studying how the skin microbiome affects predisposition and progression. Specific gut microbes have been implicated in the outcomes for immunotherapy response in melanoma skin cancer, supporting a role of systemic immune interactions via the gut in potentiating immunotherapy response.

However, because many aspects of cutaneous immunity are compartmentalized from systemic immune effects, we hypothesize that the skin microbiome could uniquely impact skin cancer outcomes during immunotherapy by modulating the cutaneous immune milieu.