Research & Publications
Dr. Bunick uses structural biology techniques called x-ray crystallography, nuclear magnetic resonance, and cryo-electron microscopy to determine the high resolution, three-dimensional structures of proteins important to both normal and diseased skin. In addition, he uses structural biology to ascertain the biochemical basis for how dermatology drugs work. Knowing the structure of various skin proteins and drug-ligand interactions enables a better understand of how a protein or therapeutic functions in normal and diseased skin states. Ultimately, it may lead to the development of novel, improved therapies or better patient care. In addition to wet-lab/basic science research, Dr. Bunick also leads clinical trial investigations at the Yale Center for Clinical Investigation in order to evaluate cutting-edge therapies and their safety and effectiveness in patients.
Specialized Terms: structural biology of skin proteins; x-ray crystallography; epidermal structure and function; structure-based drug design; cryo-EM; NMR; clinical trial;
Extensive Research Description
Principal Investigator Background
Dr. Christopher Bunick, MD, PhD, is an Associate Professor of Dermatology performing dermatologic research studying the three-dimensional structures of skin-related proteins using primarily x-ray crystallography and cryo-electron microscopy. Dr. Bunick has over 25 years of experience in the field of structural biology. He leads a structural biology research program in the dermatology field, with a specific niche: “atomic resolution dermatology.” Dr. Bunick’s research focuses on determining the atomic resolution structures of proteins, protein complexes, and drug-ligand complexes that are essential to formation of a functional human skin barrier or the action of a precision medicine therapy. He uses x-ray crystallography and cryo-electron microscopy to: 1) determine the high resolution, three-dimensional structures of proteins important to both normal and diseased skin, and 2) determine the mechanism of action of how dermatology drugs bind their molecular target. Knowing the structure of various skin proteins and drugs enables a better understanding of how a protein or therapeutic functions in normal and diseased skin states. Ultimately, it may lead to the development of novel therapies or better patient care.
Areas of Active Basic Science Research
The Bunick lab applies biochemistry, structural biology (X-ray crystallography, Cryo-EM), and cell biology techniques to investigate biological processes of human skin. As a board-certified and practicing dermatologist, Dr. Bunick tackles scientific questions that can improve clinical care of patients. We have ongoing cutting edge translational research in the following areas:
1. Molecular mechanisms of intermediate filament (IF) assembly.
IFs, which include keratins, are fundamental filamentous assemblies that comprise the cellular cytoskeleton, regulate cellular signaling, and form an essential component of the human skin barrier. The Bunick lab discovered a novel assembly mechanism shared among IFs, and we continue to investigate the function of IFs.
2. Molecular mechanisms of human skin barrier integrity.
Keratin IFs regulate the human skin barrier through two key processes: i) filaggrin aggregation of keratins to form an impermeable proteinaceous barrier in the stratum corneum, and ii) keratins bind desmoplakin at desmosomes to enhance cell-cell adhesion in the epidermis. The Bunick lab has determined the only filaggrin structure and 75% of all keratin structures to date, and investigate the mechanisms of keratin assemblies in skin barrier function.
Two recent proteins studied are human profilaggrin and the keratin 1/10 complex because of their importance to skin barrier integrity and association with clinically relevant skin diseases. The NIH/NIAMS website estimates up to 90 million Americans suffer from some form of atopic dermatitis. Atopic dermatitis and other forms of severely dry skin, such as ichthyosis vulgaris, are associated with defects or mutations in profilaggrin and its processed fragment, filaggrin. Similarly, mutations mapped to keratins 1 or 10 are linked to several clinical disorders of keratinization (keratinopathies). Work on these proteins led to a 2.2 Å resolution crystal structure of the profilaggrin S100 calcium-binding domain and several 2.0 Å to 3.3 Å resolution crystal structures of complexes between the 1B and 2B helices of K1 and K10.
3. Acne vulgaris pathogenesis and mechanisms of drug therapy.
Building from our structure of the acne drug sarecycline bound to the 70S ribosome, we investigate how acne drugs function in their pathogenic target, Cutibacterium acnes, and how that impacts clinical efficacy and antibiotic resistance. We investigate how C. acnes regulates the microbiome niche of the pilosebaceous unit.
4. Molecular mechanisms of skin therapeutics in patient care.
Dr. Bunick's lab works to understand the biochemical mechanisms of dermatologic drugs. Recent work on the structural mechanism of the acne vulgaris drug sarecycline was published in PNAS, and there are ongoing drug development projects in the lab in acne vulgaris, psoriasis, atopic dermatitis, cancer, and more.
Dr. Bunick currently is funded by the NIH/NIAMS (R01 Award) and a research grant from Almirall. His laboratory is open to medical students, graduate students, and post-docs motivated by and passionate for applying biochemistry and structural biology to skin disease.
Graduate & Medical Students, Post-docs, and Mentorship
Dr. Bunick's lab is committed to providing a highly intellectual and fun environment to develop the research skills necessary to succeed in life, whether in academia, industry, or elsewhere. We teach students the key processes used in our research, including protein production and purification, biochemical assays, structure determination techniques, and clinical/translational thinking. Dr. Bunick is faculty in the Yale Program in Translational Biomedicine, and participtes in the BBS Track: Translational Molecular Medicine, Pharmacology, and Physiology (TMMPP).
Dr. Bunick works with the Yale Center for Clinical Investigation to lead clinical trial investigations on promising new dermatology therapeutics. Trials to date include:
-VAPAUS: A Multicenter, Phase 3 Randomized, Double-Blind, Vehicle-Controlled Study Evaluating the Safety and Efficacy of PTX-022 in the Treatment of Pachyonychia Congenita.
-TMB01-301: The ASCEND Study: A Phase III, Multicenter, Double Blinded Vehicle Controlled Study of TMB-001 - with a Parallel Optional Maximal Use Arm - in the Treatment of RXLI (X-linked) or ARCI Ichthyosis in Subjects Aged ≥ 6 Years.
-A randomized, parallel, double-blind, vehicle-controlled study to evaluate the safety and efficacy of two different concentrations of topical TMB-001 for the treatment of congenital ichthyosis.
-A randomized, bilateral comparison, vehicle-controlled, safety and tolerability study of topical PAT-001 for the treatment of congenital ichthyosis.
Biochemistry; Biophysics; Dermatitis, Atopic; Dermatology; Epidermis; Intermediate Filaments; Keratins; Molecular Biology; Skin; Ichthyosis Vulgaris; Crystallography, X-Ray; Computational Biology; Proteomics
Public Health Interests