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Research Profile: Frank W. LoGerfo, MD, and Leena Pradhan-Nabzdyk, PhD
About Dr. LoGerfo and Dr. Pradhan-Nabzdyk
Mauricio Contreras, MD
Jennifer Li, MD
Navneet Momi, PhD
Kimberly Piper, MS, MA
Our group has been extensively involved in different areas of vascular biology, diabetes, and neuropeptide research: 1) evaluating mechanisms responsible for the development of intimal hyperplasia (IH) in vein grafts and prosthetic grafts; and 2) developing novel techniques to prevent IH in both vein grafts and prosthetic grafts using bioengineering methodologies.
IH is the most common cause of delayed prosthetic arterial graft failure and delayed failure of vein grafts. As graft healing occurs, genes are either up- or down-regulated as compared to a quiescent arterial wall. Our lab studies altered gene expression that results in endothelial cell activation as well as cellular proliferation, migration, and extracellular matrix production by smooth muscle cells, leading to vein graft IH and anastomotic IH (AIH).
Based on our previous work, the LoGerfo-Pradhan group has identified gene targets that are altered in both vein graft IH and AIH. Current work is focused on understanding the biology of these molecules, including Thrombospondin-2 (TSP-2) and interleukin (IL)-18, and developing techniques to deliver silencing RNA (siRNA) to the vessel wall to silence those targets and thereby mitigate the development of IH. Results from these projects have been presented at several national and international meetings and have led to manuscripts.
In collaboration with Drs. Christiane Ferran and Manoj Bhasin of BIDMC, we conducted single cell genomics in a canine model of vein graft IH. This work, which is currently ongoing, will be first such single cell genomics study in the field. Based on these preliminary results, our group successfully renewed its R01 funding for this project. Additionally, the metabolomics results have backed these genomic alterations and efforts made to increase the overall sample size. During the pandemic, a meta-analysis study was conducted on vein graft failure research aiming to discover signature genome targets for IH prevention. The results have been presented at various international and national meetings by postdoctoral fellow Navneet Momi.
The prosthetic IH project, being conducted in collaboration with Drs. Christiane Ferran of BIDMC and Dr. David Mooney (Harvard John A. Paulson School of Engineering and Applied Sciences), is focused on developing Click-Hydrogels that can be coated on clinically used prosthetic grafts as dacron to deliver siRNA at the anastomotic site in an in vivo rat carotid angioplasty model. The group is also working on designing a double-sided tape to secure the gel for improved siRNA delivery and optimizing its flexibility and impermeable backing in vitro. The results from this project have been presented at national and international meetings by postdoctoral fellows Cindy Hyunh, Patric Liang, and Jennifer Li.
Additionally, human aortic thrombus specimens have been collected and biobanked for ongoing aortic aneurysm thrombus evaluation for inflammatory markers and microbiome analysis.
Through NIH R21 funding, Dr. Pradhan-Nabzdyk, in close collaboration with Dr. Lijun Sun of BIDMC, has discovered several small molecule inhibitors of the pro-inflammatory cytokine, IL-18. IL-18 is implicated in many chronic conditions including ulcerative colitis, cardiovascular disease, psoriasis, and various cancers. In addition to testing the efficacy of these inhibitors in vascular disease models, Drs. Pradhan-Nabzdyk and Sun are collaborating with colleagues in the BIDMC divisions of gastroenterology and colon and rectal surgery to test the efficacy in patient samples of ulcerative colitis. The data from these experiments are extremely promising and have gained special interest from industrial companies regarding inhibitor IC50s. A provisional patent application has been filed for these molecules.
Teaching, Training, and Education
We have mentored several students and postdocs in the lab. Additionally, Drs. LoGerfo, Pradhan-Nabzdyk, and Ferran are the Co-program Directors of the NIH T-32 Harvard-Longwood Research Training Program in Vascular Surgery. This two or three-year research training program is the oldest such program in vascular surgery in the country. Currently there are eight trainees (seven surgical residents and one PhD postdoctoral fellow) mentored in different labs in the Longwood Medical Area. Trainees from around the country apply to this program and, thus far, 87 trainees have graduated from the program. This grant was successfully renewed for years 26-30.
In addition, Drs. LoGerfo and Pradhan-Nabzdyk co-direct the NIH T-35 program, the Harvard-Longwood Short-Term Research Training Program in Vascular Surgery. Now in its eighth year, this 10 to 12-week summer program trains medical students in vascular surgery research. Medical students from across the country apply to this program and conduct research in various labs in the Longwood Medical Area. To date, 50 students have graduated from this program.
Abstracts, Posters, and Exhibits
Liang P, Mooney D, Pradhan-Nabzdyk L, LoGerfo F. Perivascular Gene Targeted Therapy Using Biodegradable CLICK-Gelatin Hydrogels. American College of Surgeons Clinical Congress 2019, San Francisco, CA (oral presentation)
Momi N, Liang P, Bhasin S, LoGerfo FW, Ferran C, Pradhan-Nabzdyk L, Bhasin M. Vein Graft Failure: Single Cell Genomics. Academic Surgical Conference, Houston TX (oral presentation)
Momi N, Bhasin S, Liang P, LoGerfo FW, Ferran C, Bhasin M, Pradhan-Nabzdyk L. Vein Graft Failure and Single Cell Genomics. 8th Annual Harvard Surgery Research Day, Boston, MA (poster)
Momi N, Bhasin M, Bhasin S, Liang P, LoGerfo FW, Ferran C, Crumb W, Contreras MA, Pradhan-Nabzdyk L. Vein Graft Failure: Single Cell Genomics and Real-Time Energetics. Center for Vascular Biology Research 15th annual retreat, Boston, MA (poster)
Momi N, Bhasin M, Bhasin S, Liang P, LoGerfo FW, Ferran C, Crumb W, Contreras MA, Pradhan-Nabzdyk L. Vein Graft Failure: Single Cell Genomics and Real-Time Energetics, 16th Academic Surgical Congress, Orlando, FL (oral presentation)
Selected Research Support
Mechanisms of Prosthetic Arterial Graft Failure. NIH, 1987-2021; PIs: Frank W. LoGerfo, MD, Christiane Ferran, MD, PhD, David Mooney, PhD; Co-Investigator: Leena Pradhan-Nabzdyk, PhD, MBA
Genetic Engineering of Vein Bypass Grafts in Vascular and Cardiovascular Surgery. NIH, 2007-2022; PIs: Frank W. LoGerfo, MD, Christiane Ferran, MD, PhD, Manoj Bhasin, PhD; Co-Investigator: Leena Pradhan-Nabzdyk, PhD, MBA
Harvard-Longwood Research Training in Vascular Surgery. NIH, 1993-2024; PI: Frank W. LoGerfo, MD; Executive Committee: Leena Pradhan-Nabzdyk, PhD, MBA
Harvard-Longwood Short-Term Research Training in Vascular Surgery. NIH, 2013-2023; (formerly William J. von Liebig Summer Research in Vascular Surgery Program, 2000-2012) Program Co-Directors: Frank W. LoGerfo, MD, Leena Pradhan-Nabzdyk, PhD, MBA
Huynh C, Shih TY, Mammoo A, Samant A, Pathan S, Nelson DW, Ferran C, Mooney D, LoGerfo F, Pradhan-Nabzdyk L. Delivery of targeted gene therapies using a hybrid cryogel-coated prosthetic vascular graft. PeerJ 2019;20;7:e7377.
Nabzdyk CS, Pradhan-Nabzdyk L, LoGerfo FW. RNAi therapy to the wall of arteries and veins: Anatomical, physiologic, and pharmacological considerations. J Transl Med 2017;28;15(1):164.
Shean KE, Soden PA, Schermerhorn ML, Zettervall SL, Deery SE, Darling JD, Hamdan A, LoGerfo FW. Lifelong limb preservation: A patient-centered description of lower extremity arterial reconstruction outcomes. J Vasc Surg 2017;66(4):1117-1122.
Bodewes T, Johnson J, Hyunh C, Muralidharan S, Contreras M, LoGerfo FW, Pradhan-Nabzdyk L. Intraluminal delivery of thrombospondin-2 siRNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model. FASEB J 2017;31(1):109-11.
Mammoo A, Bencheriff SA, Nabzdyk C, Shih TY, Huynh C, Mooney DJ, LoGerfo FW, Pradhan-Nabzdyk L. Heparin containing cryogels as surfaces for local cardiovascular drug delivery. Polymers; in preparation.