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4^th year graduate student in the laboratory of Dr. David A. Dean.

"Role of MRCKa and Na+, K+-ATPase Signaling in Alveolar Barrier Function in the Mouse Lung"

Project Summary: Acute Respiratory Distress Syndrome (ARDS) is a severe medical condition, which is characterized by significant alveolar fluid accumulation and insufficient gas exchange. Cardiac surgery, ECMO, and use of cardiac medications are all known risk factors for ARDS which also complicates management of these and other cardiovascular diseases. Effective alveolar fluid clearance and repair of a functional alveolar-capillary barrier are considered the primary mechanisms for edema resolution in ARDS. Apart from enhancing fluid clearance, the Na+,K+-ATPase has been shown important for alveolar barrier function. Our lab showed that overexpression of the Na+,K+-ATPase b1 subunit into lungs enhances alveolar barrier integrity in previously injured lungs in mice and pigs. Previous in vitro data indicated that MRCKa mediates the upregulation of tight junction (TJ) proteins and epithelial barrier integrity by b1 overexpression. I hypothesize that the b1-Na+,K+-ATPase regulates alveolar barrier function through MRCKa in vivo. I will determine 1) whether MRCKa is required for the upregulation of TJ proteins and barrier function by b1 gene delivery in vivo, and 2) whether overexpression of MRCKa alone is sufficient to protect and/or treat lipopolysaccharides (LPS) induced lung injury in mice. LPS will be delivered by oropharyngeal aspiration to induce lung injury. Various plasmids will be delivered to mouse lungs by electroporation. For aim 1, plasmid to knockdown MRCKa or an MRCKa inhibitor will be delivered to lungs 24 hours before gene transfer of plasmid to overexpress b1. If required for signaling, MRCKa knockdown or inhibition will abolish b1's induction of TJ proteins and barrier upregulation. For aim 2, mice will be challenged with LPS 24 hours after (protection study) or before (treatment study) gene transfer. At end points, various assays will be performed to assess lung injury. It is expected that overexpression of MRCKa alone will be sufficient to protect and treat LPS induced acute lung injury, decreasing lung injury and increasing TJ expression; overexpression of both MRCKa and b1 subunit will augment the protection and treatment of LPS injured lungs to give the greatest reduction in lung injury and improvement in barrier function. These studies will increase our understanding of the pathogenesis and treatment of ARDS, improve lung health, and ultimately decrease cardiovascular complications.

5^th year graduate student in the laboratory of Dr. Chen Yan.

"The Role of PDE1C in Vascular Smooth Muscle Cell Lysosomal Dysfunction and Atherosclerosis"

Project Summary: The objective of this project is to investigate the function and underlying mechanism of the cyclic nucleotide phosphodiesterase 1C (PDE1C) in pathological vascular remodeling during atherogenesis. Cyclic AMP and cyclic GMP regulate vascular functions. PDEs by hydrolyzing cyclic nucleotides, regulate cyclic nucleotide signaling. Vascular smooth muscle cells (SMCs), upon endothelium damage, transit from contractile phenotype to synthetic phenotype. In vasculature, PDE1C expression is selectively induced in synthetic SMCs, but not in contractile SMCs or endothelial cells. Synthetic SMCs can accumulate oxidized low-density lipoprotein (oxLDL) in lysosomes, referred to as SMC-derived foam cells, that have been suggested to contribute significantly in atherosclerotic lesions. oxLDL accumulation in lysosome causes lysosome membrane permeabilization and lysosome dysfunction, which accelerates atherosclerosis progression. Our preliminary data demonstrate PDE1C deficiency significantly decreases atherosclerotic lesions in vivo. In synthetic SMCs in vitro, we found that PDE1C inhibition reduces lysosomal oxLDL accumulation and ameliorates lysosomal permeabilization. Therefore, we propose two specific aims. Aim1: Determine the roles and underlying mechanisms of PDE1C in the regulation of oxLDL accumulation and lysosomal permeabilization in synthetic SMCs in vitro. In SMCs culture, PDE1C deficiency will be examined by PDE1 activity inhibitor, PDE1C wildtype vs PDE1C knockout mouse SMCs, PDE1C shRNA, and PDE1C reconstitution by adenovirus. SMCs oxLDL accumulation and lysosomal permeabilization will be assessed by Acridine Orange staining, cathepsin B/D staining, and lysosomal galectin puncta assay. Underlying mechanistical studies will use pharmacological inhibitors, siRNA or shRNA. Aim2: Evaluate the effect of PDE1C deficiency on SMC lipid accumulation and lysosomal dysfunction in atherosclerotic lesions in vivo. We will use spontaneous atherosclerotic model induced by 4 months high fat diet in mouse for biochemical assessments in the lesion areas. We will also examine the treatment potential of PDE1 inhibition on pre-trapped lipid deposition, using an accelerated atherosclerosis mouse model induced by carotid artery partial ligation. We hypothesize that PDE1C plays an essential role in atherosclerotic vascular modeling by promoting oxLDL induced-lysosomal dysfunction in synthetic SMC. This study may have significant therapeutic impact on atherosclerosis treatment.

Matthew Rook, 2nd year graduate student in the laboratory of Dr. David M. MacLean was awarded a BPS Travel Award to attend the Biophysical Society's 64th Annual Meeting in San Diego, California, February 15-19, 2020.

Matthew will be presenting his poster titled "Stoichiometry of Acid-Sensing Ion Channel (ASIC) Pharmacology".

For more information on the conference, please visit the Biophysical Society website.

Five graduate students from the University of Rochester Medical Center and one graduate student from the School of Arts and Sciences have been offered National Institutes of Health F31 fellowship grants. The grants are part of a federally sponsored program that provides three years of support for students pursuing doctoral or other research-based degrees in health-related areas.

The purpose of the grants is to enhance diversity in the health-related research workforce by supporting the research training of predoctoral students from diverse backgrounds. Candidates must demonstrate outstanding scholarly promise in health-related research, be enrolled in a research doctoral degree program, have identified a research project, and made a commitment to a career as either an independent research scientist or as an independent physician-scientist or other clinician-scientist (dual-degree training) to be eligible to apply.

John Bachman '19M (MS) is a PhD candidate in the cell biology of disease (pathology) program at the Medical Center, under the direction of Joe Chakkalakal, a dean's associate professor of pharmacology and physiology. Bachman's research focuses on the consequences of radiation therapy on juvenile muscle stem cells. "By learning how radiation impacts developing muscle, we can use that information to help cancer survivors lead better and stronger lives," he says. Bachman is a native of Hazleton, Pennsylvania, and would like to pursue a postdoctoral position with the goal of becoming an independent investigator.
Project title: "Targeting p21 To Stimulate Irradiated Muscle Stem Cell Function and Muscle Regeneration"

Emily's Entourage (EE) is incredibly honored to have a group of scientists dedicated to accelerating research and drug development for nonsense mutations of Cystic Fibrosis (CF). In the next year, 90% of the CF population could see the benefits of a life-saving drug on the market (currently pending FDA review and approval), but those in the final 10%, including those with nonsense mutations, will not benefit from these new breakthrough drugs.

And in fact, the commitment of the scientists run so deep that it is not merely limited to their "day job" at the lab advancing critical research. Rather, at times, it permeates many aspects of their lives. There is no better example of that than University of Rochester's John Lueck, PhD, who has decided not only to do research to speed breakthroughs and a cure for the final 10%, but also to raise the funds that will drive the critical research.

Over the last few months, Dr. Lueck has trained to climb The Matterhorn in the Swiss Alps, a mountain he tackled on August 22 that reaches almost 15,000 feet high. As a two-time EE grantee through the Catalyst for a Cure Campaign, he flipped the script and committed to raise funds for EE throughout the entire training process!

Liwei Wang, Ph.D. Graduate of the Cellular and Molecular Pharmacology and Physiology PhD Program won the Fenn Award for best thesis, the award was presented at the 2019 Commencement Dinner by Richard Libby, Senior Associate Dean for Graduate Education and Postdoctoral Affairs following an introduction from Dr. Wang's faculty mentor, Dr. David Yule.

The award was for Dr. Wang's thesis, entitled "Region-specific Proteolysis Differentially Regulates Inositol 1,4,5-trisphosphate Receptor Activity " Dr. Wang is currently a Postdoctoral Fellow in the laboratory of Prof. Stefan Feske at NYU, Langone Medical School. His current research involves investigating the role of ion channels in immunological tolerance and immunity.

About the Award

Dr. Wallace Fenn was a Professor of Physiology at the University of Rochester School of Medicine and Dentistry from 1924 to 1961. He served as the Chairperson of the Department of Physiology from 1924 to 1959 and thereafter until his death in 1971, he was appointed by the University to the position of Distinguished University Professor of Physiology. As well, Dr. Fenn served as the Associate Dean of Graduate Studies from 1957 to 1959.

To read more regarding this award, please visit the department of Biochemistry and Biophysics website.

Romeo Blanc postdoctoral fellow in the Chakkalakal Lab was the recent recipient of the Podium presentation, Travel award, and Merit Awards from the International Society for Stem Cell Research (ISSCR) for the upcoming annual meeting in Los Angeles CA, June 26 -- June 30, 2019.

The first award, called Travel Award, came from the ISSCR itself and covers registration and/or cash award. The second award, called Abstract Merit Award is made to highlight some outstanding selected abstract which is chosen by ISSCR as well.

Congratulations Romeo!

To fortify the involvement of graduate students in academic affairs, the Department of Pharmacology and Physiology (CMPP) hosted student nominated guest speaker: Dr. Ehsan Sarafraz-Yazdi, Ph.D., M.P.H., Founder and CEO of NomoCan Pharmaceuticals, LLC. Dr. Yazdi was nominated by PhD candidate Edward Ayoub and chosen by CMPP graduate students to spend a day at URMC. During his visit, Dr. Yazdi connected with faculty and students, and presented a seminar highlighting a new microfluidic system to study anti-cancer drug responses ex-vivo. Dr. Yazdi also shared his vision and inspiration to start his own pharmaceutical company at a URBEST Career Story hosted by Dr. Tracey Baas. CMPP will continue to host a student-nominated guest speaker annually.

Left to right: Lily Cisco, Dr. Ehsan Yazdi, Edward Ayoub, Kai Ting Huang, Alexander Milliken, Matthew Rook

Pharmacology & Physiology and BME professor, Denise Hocking has been honored with a UR Research Award for her project, Bacterial Pathogens, Fibronectin Mimicry and Intestinal Permeability.

Research in the Hocking lab focuses on understanding the mechanisms by which the extracellular matrix protein, fibronectin, affects cell and tissue functions that are critical for wound repair. We study both the structural mechanisms and intracellular signaling events that mediate cell and tissue responses to matrix fibronectin. In turn, we are using this information to develop novel technologies for tissue engineering, and therapeutic approaches to promote tissue regeneration in chronic wounds.

Congrats Denise!

Dr. Jean Bidlack, Professor of Pharmacology and Physiology, received the Herman Friedman Founder's Award from the Society on NeuroImmune Pharmacology. This award was given for "Visionary Contributions in Establishment and Continued Development of the Society. The award was presented at the 25th Annual Meeting of the Society on NeuroImmune Pharmacology in Portland, Oregon in April 2019.

Since Debra Andreacchi-Roth began her career at the University in 1976, she has distinguished herself through her exceptional leadership, organizational skills, and mentorship, most recently in service to the Departments of Pharmacology and Physiology, and Anesthesiology and Perioperative Medicine.

As senior administrator and research program manager in the Department of Pharmacology and Physiology, Andreacchi-Roth promotes a goal-driven environment, fosters professional relationships across various departments, serves key institutional committees and special interest groups, and "works tirelessly to create a friendly and welcoming work environment that promotes teamwork, ICARE values, and commitment to a common purpose," wrote Robert Dirksen, the Lewis Pratt Ross Professor and Chair of the Department of Pharmacology and Physiology, in a letter of support. Lori White, an administrator in the department and member of the nominating team, said "I consider myself very fortunate to be under her leadership the past 27 years."

In 1996, Andreacchi-Roth orchestrated the merger of the pharmacology and physiology departments, combining two administrative offices, their resources, and workflows into a new and successful administrative structure. She initiated the Sponsored Research Business Center under the Department of Pharmacology and Physiology in 2001, to assume pre- and post-award management of research awards for the Department of Anesthesiology and Perioperative Medicine—a seamless transition due to her strong organizational and leadership skills.

In her current role, Andreacchi-Roth oversees the fiscal and operational activities in the Department of Pharmacology and Physiology and is responsible for all proposal submissions and grant post-award activities for the department and the business center. She is widely recognized for treating all researchers with the same level of dedication, energy, and skill.

"Debe is the single most important person providing support to the funded investigators in our department," wrote Laurent Glance, a professor and vice chair for research in the Department of Anesthesiology and Perioperative Medicine and professor in Public Health Sciences, in a letter of support. "She is the most hardworking and dedicated administrator I have ever worked with."

Michael Golinkoff (left), one of the founders of Emily's Entourage; Phil Thomas (middle), cystic fibrosis researcher at UT Southwestern, John Lueck (right), assistant professor of Pharmacology and Physiology at URMC.

There are all sorts of "typos" in our DNA that can lead to disease. One kind of typo -- a premature termination codon or PTC -- is responsible for 10 to 15 percent all genetic diseases, including cystic fibrosis and Duchenne muscular dystrophy. PTCs lead to the production of short and often deleterious proteins.

A recent paper by John Lueck, Ph.D., assistant professor of Pharmacology and Physiology and Neurology, shows how high-throughput screening may be used to fix these typos and lessen disease severity. Published in Nature Communications, the study found that modifying tRNA (a type of RNA molecule that helps convert messenger RNA or mRNA into protein) can help the cell make a full length protein, even with a PTC in the middle of the gene. With this new technology to modify tRNA, the authors were able to use gene therapy to suppress faulty versions of a gene in skeletal muscle, and instead force the cells to produce a full-length protein.

At the moment, most investigational therapies for inherited diseases are focused on small molecules, which to this point have not been successful. "For many of these diseases, including cystic fibrosis and Duchenne muscular dystrophy, there are no therapies and patients rely on palliative care," explains Lueck. "Our engineered tRNA platform puts another iron in the fire for development therapeutics and we're hopeful that the technology can be translated into a viable treatment for patients in the near future."

While these studies are still in the early stages, Lueck was recently awarded a unique pilot grant from Vertex Pharmaceuticals to continue this work. This work was funded by Emily's Entourage and the Cystic Fibrosis Foundation and accomplished with the collaboration of researchers at the Cystic Fibrosis Foundations Therapeutics Lab, the Wistar Institute, University of Iowa, and Integrated DNA Technologies, Inc.

Emily's Entourage (EE) is delighted to learn that John Lueck, PhD was recently given a Vertex CF Research Innovation Award of $750,000 over three years to further his research on nonsense mutations of Cystic Fibrosis (CF). In 2017, through the "Catalyst for a Cure Campaign," EE funded research done by Dr. Lueck, Chris Ahern, PhD, and Paul McCray, MD that focused on using engineered transfer-RNA molecules to genetically repair the W1282X-CFTR nonsense mutation. We are pleased that Dr. Lueck has been given the opportunity to continue this critical groundwork:

"EE's funding brought me into the field of CF research with the specific focus to develop technology for treatment of W1282X. Through the enriching EE scientific community, we have formed collaborations that have propelled our research into new exciting directions that otherwise would not have been explored. Using our results obtained through EE funding as a foundation, we're working to develop optimal delivery methods of our engineered tRNA platform to target nonsense mutations within the CFTR gene in human airway epithelium."

Congratulations, Dr. Lueck, on this incredible award! We're so grateful for your steadfast commitment to accelerating breakthroughs for nonsense mutations of CF! Thank you for seeing beyond to a better future for everyone with CF!

Emily's Entourage is an innovative 501(c)3 foundation that accelerates research for new treatments and a cure for nonsense mutations of Cystic Fibrosis, a fatal genetic disease afflicting Emily and many others. Named a Champion of Change for President Obama's Precision Medicine Initiative, Emily's Entourage has awarded over $3.4 million in research grants since 2011 and led worldwide efforts to drive high-impact research and drug development.