November 22, 2024

Zoey successfully defends thesis

Congratulations to Zoey, who is now Dr. Zoey! She successfully defended her PhD thesis on Nov 22nd!  She did a great job, and we're all very proud!


November 13, 2024

Ines and Joel's paper online at IFAR

Inès and Joel have a great paper available online (open access, so freely available) today at International Forum of Allergy and Rhinology!  They studied bitter beta-acids from hops (yes, the same hops used for beer).  We hypothesized that these compounds (lupulone and colupulone) might be beneficial by both activating bitter taste receptors (taste family 2 receptors, or T2Rs) in the nose to stimulate beneficial innate defense responses. These compounds,  often referred to as "antibiotics" in older medical literature, also have antibacterial properties. Lupulone and colupulone were used for tuberculosis in people after World War II, but they were abandoned in favor of conventional antibiotics as antibiotics improved for TB, and because the beta-acids had some gastrointestinal side effects. Inès and Joel carried out a very rigorous and interesting study using a variety of techniques, including fluorescent biosensors, live cell imaging of indicator dyes, biochemistry, microbiology, etc. in both primary nasal cells and nasal cancer cells.     

They found that while lupulone and colupulone are bactericidal against methicillin-resistant Staph. aureus (MRSA), these compounds also have detrimental impacts on nasal epithelial mitochondria and cilia function. This is possibly because they activate a new T2R isoform, T2R1, which does not have strict cilia localization like many of the other T2R isoforms we studied in nasal epithelial cells. Lupulone and Colupulone also stimulated robust remodeling in primary cells differentiated at air-liquid interface. Epithelial remodeling is the process by which the cells that make up the epithelium change in type and/or composition. Remodeling occurs in a variety of airway diseases like chronic rhinosinusitis or cystic fibrosis. While lupulone and colupulone specifically don't look promising for development as new topical T2R-targeting or antibacterial therapies, this work sheds new light onto how T2Rs signal in the nose, including new mechanisms of how they might impinge on epithelial remodeling.  This study demonstrates that we don't yet know everything about what T2Rs do in the nose. Derivatives of these compounds might also be useful if analogues can be made to not activate T2R1 but still have anti-MRSA properties.

July 26, 2024

Zoey's GLUT1 paper now online

Zoey's second paper is now online at Cell Death Discovery!  She studied how a GLUT1 inhibitor causes apoptosis in head and neck cancer cells.  At lower concentrations, this GLUT1 inhibitor also sensitizes cancer cells to bitter taste receptor agonists to enhance their apoptotic effects.  Great work Zoey!  Another important contributor to this work (and second author!) was our Penn IDEAL SUIP student Sahil Muthuswami. You can read the open access (freely available) paper online here.


  


November 22, 2023

Zoey's paper online

Zoey's paper on lidocaine activation of T2R14 in head and neck cancer is now online at Cell Reports and was spotted on AppleNews and in Newsweek.  Congrats, Zoey!




November 2, 2023

August 1, 2023

Welcome Jordan and Alex

We welcome Jordan Williams (Penn PGG grad student) and Alex Simon (Penn Postdoc) who are starting in the lab this week.  We're excited that you are both here!

June 30, 2023

Zoey wins Blavatnik Fellowship

We're very proud that Penn Pharmacology grad student Zoey Miller from our lab was just awarded a prestigious Blavatnik Family Fellowship, generously sponsored by The Blavatnik Family Foundation, which will support her to work on T2R bitter receptors in HNSCCs over the coming academic year. Congratulations Zoey! This is one of the most prestigious awards given to Penn Biomedical Graduate Studies students. We are very grateful for generosity of Blavatnik Family Foundation supporting these awards, and very grateful they also saw what we already knew: that Zoey was incredibly deserving of the award. Great job!


May 17, 2023

New Review

Postdoc Inès wrote a very nice and very comprehensive review on T2Rs in host-pathogen interactions, just published in Microorganismshttps://www.mdpi.com/2076-2607/11/5/1295



April 24, 2023

AChemS 2023

Zoey and Rob represented the lab at the 2023 AChemS meeting in Florida. It was great to catch up with colleagues and learn about lots of new exciting taste research!  Zoey's poster was very well attended (there was a line) and Rob got some great questions after his talk. All in all, it was a successful trip!  



December 17, 2021

Postdoc Openings

We have space and funding for at least two new postdocs in the lab.  Funding is available for a postdoctoral fellow to study epithelial signaling in innate immunity, specifically how G-protein coupled receptors activate antimicrobial responses in nasal and lung cells. Another postdoctoral position is available to study GPCR taste receptor signaling in immune cells like macrophages and dendritic cells.  

Our lab uses a combination of live-cell and confocal imaging, biochemistry, and molecular biology approaches using primary human cells isolated from nasal surgical samples and cultured at air-liquid interface. A main focus of our lab is bitter taste receptors, which are expressed in many tissues beyond just the tongue, where they serve largely unknown roles. In the airway, bitter taste receptors detect bacterial products and activate calcium-driven innate immune responses.  In macrophages, bitter taste receptors receptors regulate phagocytosis through calcium and nitric oxide signaling.   

Our lab is located within the Division of Rhinology in the Department or Otorhinolaryngology. More about our lab’s research, equipment and resources, and recent publications by students and postdocs, can be found at www.robleelab.com

The postdoc will work closely with the PI and other lab members and receive training in live-cell imaging and other techniques as needed, potentially including measurements of calcium, nitric oxide, pH, ciliary beat frequency, fluid secretion, phagocytosis, and/or imaging of fluorescent protein biosensors. The postdoc will also be expected to independently or collaboratively develop or learn new techniques as required by the project. Opportunities for professional development (grant writing, review writing, collaborations, conferences, etc.) will be encouraged and supported. Salary and benefit information (based on NIH NRSA stipend levels) and information about postdoctoral policies at Penn are outlined on the Biomedical Postdoctoral Programs website.

A PhD in a biological science (cell biology, molecular biology, immunology, physiology, etc.), with demonstration of successful completion of thesis project. Experience in cell culture, biochemistry, and/or imaging is highly desirable, but not required. Communication skills (reading, writing, speaking), enthusiasm, and good interpersonal skills are essential. We encourage individuals from underrepresented racial and ethnic groups, and individuals from socially, culturally, economically, or educationally disadvantaged backgrounds to apply.

Please email a cover letter and CV, including publications and the names of three references, to Rob (rjl [at] pennmedicine [dot] upenn [dot] edu).

November 8, 2021

New paper online at Cell Calcium

Derek's paper is now online at Cell Calcium (McMahon, et al., https://doi.org/10.1016/j.ceca.2021.102499). 


Years of tenacious work revealed important changes in T2R signaling that occur with airway epithelial squamous de-differentiation. This paper is a tour-de-force of live cell imaging of indicator dyes and genetically encoded targeted probes for subcellular calcium imaging.  We're very proud of this work, and it may reveal novel pathogenic mechanisms in disease where airway de-differentiation occurs, such as COPD, asthma, or chronic rhinosinusitis.  

Rather than activating calcium in cilia to increase NO production and ciliary beating, T2R activation in non-ciliated airway cells induces strong nuclear calcium responses that propagate to the mitochondria.  This results in mitochondrial depolarization, caspase activation, and apoptotic cell death. This may be a last-resort defense against bacterial infection. However, it may also increase susceptibility of de-differentiated or remodeled epithelia to damage by bacterial metabolites. Moreover, the T2R-activated apoptosis pathway occurs in airway cancer cells. T2Rs may thus contribute to microbiome-tumor cell crosstalk in airway cancers. Targeting T2Rs may be useful for activating cancer cell apoptosis while sparing surrounding tissue.  

Congrats, Derek!

November 1, 2021

New paper online at Molecular Oncology

Ryan's paper is now online at Molecular Oncology (Carey, et al., https://doi.org/10.1002/1878-0261.13131).  



This paper goes from sub-cellular calcium imaging to patient outcomes, showing important roles for T2Rs in head and neck cancer.  We're very proud of this awesome paper!  Congrats Ryan!

September 27, 2021

New paper online at Nutrients

Ryan Carey has a paper with out today in Nutrients: "Neuropeptide Y Reduces Nasal Epithelial T2R Bitter Taste Receptor–Stimulated Nitric Oxide Production" Great work, Ryan!  https://doi.org/10.3390/nu13103392

In a nutshell, NPY may be elevated in the airways in sinus diseases or in asthma. NPY is also one of few negative regulators of airway cilia beating (via NPY2R receptors and PKC). This paper shows the same NPY2R/PKC pathway reduces cilia bitter receptor NO, linking NPY with impaired innate defense.

Airway neuropeptides (NPY, VIP, SubP, etc.) have diverse effects via GPCRs on airway epithelial & immune cells. While likely important for airway physiology & pathophysiology, we still don't know enough about how they influence these cells. Because T2R bitter receptor signaling to eNOS and production of NO controls other responses (like macrophage phagocytosis), NPY (or related PP or PYY) may also reduce T2R-mediated responses in other tissues (but likely depends on NPYRs expressed there). How do other neuropeptides regulate T2R responses in the airway? Stay tuned.

September 1, 2021

Congrats Zoey!

Congratulations to Zoey on an excellent PGG post-rotation talk to end her first year of grad school.  That's a huge accomplishment in normal times let alone a pandemic.  Way to go, Zoey!

August 22, 2021

Welcome Jenn!

Year-out Penn med student Jenn Jolivert joined the lab to help work on bitter receptors in head and neck cancer over the year.  Welcome Jenn!  We hope you have a great research experience!