Congratulations to Tim Smyth for his first authored publication "Diesel exhaust particle exposure reduces expression of the epithelial tight junction protein Tricellulin", published in Particle Fibre Toxicology in October 2020. This research article reports the new finding that diesel exhaust particles lead to epithelial barrier dysfunction, and inhibit expression of the tight junction protein Tricellulin both in vitro and in vivo.

When the first COVID-19 cases hit the University of Rochester Medical Center's ICU back in March of 2020, there were no proven treatments available, but experimental therapies were cropping up around the world. Quickly, a team of URMC clinicians and researchers mobilized to bring the most promising clinical trials - that address the broadest swath of patients' needs - to URMC. Since then, URMC has joined three clinical trials that provide extra treatment options for some of the sickest COVID-19 patients.

COVID-19 causes a wide range of outcomes: some infected people never show a single symptom, while many battle the disease for weeks in the ICU. The difference between those outcomes seems to lie in a careful balance of the immune response. In the beginning of the disease, the immune system helps fight off the virus. But for those who land in the hospital, this early, helpful immune response gives way to uncontrolled over-activation of the immune system, causing system-wide inflammation and severe complications.

The three COVID-19 inpatient clinical trials currently running at URMC attack the disease at both ends of this balance.

"Our goal has always been to promote effective therapies through clinical trials," said Martin Zand, M.D., Ph.D., senior associate dean for Clinical Research and co-director of the Clinical & Translational Science Institute. "Our team is working hard to make sure that the trials we bring to URMC have the greatest chance of benefiting our own patients, and significantly advancing the science of COVID-19 to benefit patients around the world."

Quieting Inflammation at All Ages

While researchers have high hopes that baricitinib can quell the over-exuberant immune activity of COVID-19, that trial is only open to patients who are 18 years old and up. Another trial, sponsored by Incyte Corp, is testing a very similar drug, called ruxolitinib, in patients as young as 12 who have very severe COVID-19 disease and need to be on a ventilator.

When the immune system runs amok in the late stages of COVID-19, the lining of the lungs can become leaky, allowing fluid to build up in the lungs' air sacs. This phenomenon, called acute respiratory distress syndrome, starves the body of oxygen and mechanical ventilation can even fail to rescue these patients.

The URMC team, led by Christopher Palma, M.D. and Steve Georas, M.D., expects to enroll up to 20 severely ill COVID-19 patients in the trial to see if ruxolitinib can keep them alive and get them off ventilators and out of the ICU sooner.

Congratulations to Lung Biology Program members Drs. Georas, Mariani and Dean who all received the following grants:

P.I.: Steve Georas, MD
NIH/NIAA

Award Number : 1 R01 AI144241-01A1

Title of Project: Novel role of protein kinase D in airway inflammation and antiviral immunity

Project Period: 3/13/20 -- 2/28/25?

P.I.: Tom Mariani, PhD

Agency: CTSI Pilot Project Program/NIH

Award Period: 7/1/20 -- 1/31/21

Total Award (TPC): $50,000

Title: Airway Biomarkers for Prediction of ARI Etiology (Internal Grant)

The overall goal of this project is to show that airway sampling will provide optimal diagnostic biomarkers for determining bacterial involvement in ARI.

P.I.: David Dean ,PhD

Agency: NIH/NHLBI

Award Period: 4/5/20- 3/31/24

Total Award (TPC): $2,298,764

Title: A multimodal delivery and treatment approach for Acute Lung Injury (R01)

This projects investigates how gene transfer of the b1 subunit of the Na,K-ATPase to the lung increases not only alveolar fluid clearance, but also improves alveolar-capillary barrier function by up regulating abundance and activity of tight and adherent junction complexes.

P.I.: David Dean, PhD

Agency: NIH/NIDDK

Award Period: 4/15/20 -- 3/31/23

Total Award (TPC): $1,588,524

Title: Gene therapy for GERD-associated esophageal epithelial barrier dysfunction (R01)

Gen transfer of the b1 subunit of the Na,K-ATPase can upregulate tight and adherence junctions abundance and activity in the lung. Since a hallmark of gastroeosphageal reflux disease (GERD) is reduced barrier function in the distal esophagus (which may play a role in ultimate transition to esophageal adenocarcinoma), this project investigates whether gene delivery of the b1 subunit of the Na,K-ATPase can restore esophageal barrier integrity and therefore reduce GERD.

P.I.: David Dean, PhD

Agency: Cystic Fibrosis Foundation

Award Period: 2-1-20 -- 1-31-23

Total Award (TPC): $840,000

Title: : Electroporation-mediated gene delivery to the airways to treat Cystic Fibrosis (grant)

This project investigates whether electroporation-mediated gene transfer can be used to effectively sustain long-term expression of CFTR in animal models. If successful, the project may lead to the development of new therapies designed to treat people with cystic fibrosis.