Research Profile: Frank W. LoGerfo, MD, and Leena Pradhan-Nabzdyk, PhD

 

Frank W. Logerfo, MD
William V. McDermott Distinguished Professor of Surgery, Harvard Medical School

 

Pradhan-Nabzdyk-LeenaLeena Pradhan-Nabzdyk, PhD
Assistant Professor of Surgery, Harvard Medical School

Research Group

Daniel Creighton
Mauricio Contreras, MD
Patric Liang, MD
Navneet Momi, PhD
Akshi Thakkar, MS

Research Focus

Our group has been extensively involved in different areas of vascular biology, diabetes, and neuropeptide research: 1) evaluating mechanisms responsible for development of intimal hyperplasia (IH) in vein grafts and prosthetic grafts; 2) developing novel techniques to prevent IH in both vein grafts and prosthetic grafts using bioengineering methodologies’ and 3) wound healing in diabetes.

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).

Dr. Pradhan-Nabzdyk’s main research focus is diabetic neuropathic complications. Peripheral neuropathy and peripheral vascular disease are the major contributors to diabetic foot ulcers and their failure to heal. Therefore, it is important to assess the individual and combined role of neuropathy and vascular disease and their intricate interplay that leads to diabetic foot ulcers (DFU).

To achieve this goal, Dr. Pradhan-Nabzdyk has successfully developed an in vivo diabetic rabbit model of ischemic and neuroischemic wound healing. She is conducting studies in rabbit models of wound healing aimed at understanding the role of neuropeptides in diabetic wound healing. Dr. Pradhan-Nabzdyk also collaborates with Aristidis Veves, MD, Division of Podiatry, using knock-out mice models to further understand the mechanisms underlying diabetic wound-healing complication.

In addition to understanding the mechanisms underlying diabetic wound healing, Dr. Pradhan-Nabzdyk is also developing novel therapeutics to treat non-healing ulcers in collaboration with Dr. Veves, Dr. Paula Hammond of the Massachusetts Institute of Technology (MIT), and Dr. David Mooney of the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Accomplishments 2016-2017

Based on their previous work, the LoGerfo-Pradhan group has identified gene targets that are upregulated 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 resulted in manuscripts. Dr. Pradhan-Nabzdyk through NIH funding is also developing small molecule inhibitors for prevention of IH.

In collaboration with Dr. Mooney, our group is developing novel heparin-based cryogels and hydrogels to which siRNA could be adsorbed. Their preliminary experiments suggest successful siRNA delivery to vascular endothelial and smooth muscle cells. Moreover, these cryogels and hydrogels could be coated upon existing clinical vascular graft materials for prevention of prosthetic graft intimal hyperplasia.

The diabetic rabbit model developed by Dr. Pradhan-Nabzdyk is being used not only to understand the mechanisms of this devastating problem, but is also being used to test therapies directed to improve wound healing. In collaboration with Harvard’s Wyss Institute, Dr. Pradhan-Nabzdyk tested the efficacy of the neuropeptide Substance P that was encapsulated in modified alginate gel in neuroischemic wound healing. The goal was to deliver Substance P in a continuous manner for a period of 10 days using the alginate gel. In collaboration with Dr. Hammond of MIT, Dr. Pradhan-Nabzdyk is testing the efficacy of drug delivery to diabetic wounds through a layer-by-layer (LbL) system developed by Dr. Hammond.

Teaching, Training, and Education

We have mentored several students and post-docs in the lab. Additionally Dr. LoGerfo is the Program Director of the Harvard-Longwood Research Training Program in Vascular Surgery NIH-T32 program and Dr. Pradhan-Nabzdyk is the member of the Training Program Executive Committee. Currently there are eight post-doctoral fellows in this program mentored in different labs in the Longwood Medical Area. Based on the success of the T-32 program and the past William J. von Liebig Summer Research in Vascular Surgery Fellowship program for medical students, we (Drs. LoGerfo and Pradhan-Nabzdyk as Co-Directors) received NIH T-35 funding in 2013 which was recently renewed for additional five years, 2018-2022. The goal of this T-35 program is to train medical students in vascular surgery research for a short (10-12 weeks) period.

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, 2013-2017; PI: Frank W. LoGerfo, MD; Co-Investigators: Christiane Ferran, MD, PhD; Leena Pradhan-Nabzdyk, PhD, MBA

Development of Small Molecule Inhibitors of IL-18 to Prevent Intimal Hyperplasia; NIH, 2016-2018; PIs: Leena Pradhan-Nabzdyk, PhD, MBA, Lijun Sun, PhD; Co-Investigator: Frank W. LoGerfo, MD

Harvard-Longwood Research Training in Vascular Surgery; NIH, 2014-2019; PI: Frank W. LoGerfo, MD; Training Program Executive Committee: Leena Pradhan- Nabzdyk, PhD, MBA

Harvard-Longwood Short-Term Research Training in Vascular Surgery; NIH, 2013-2018; Program Co-Directors: Frank W. LoGerfo, MD; Leena Pradhan-Nabzdyk, PhD, MBA

Mechanisms of neuropeptides action in diabetes; NIH, 2011-2016; Co-investigators: Frank W. LoGerfo, MD, Leena Pradhan-Nabzdyk, PhD, MBA

Selected Publications

You JO, Rafat M, Almeda D, Maldonado N, Guo P, Nabzdyk CS, Chun M, LoGerfo FW, Hutchinson JW, Pradhan-Nabzdyk LK, Auguste DT. pH-responsive scaffolds generate a pro-healing response. Biomaterials 2015;57:22-32.

Nabzdyk CS, Chun M, Pathan SG, Nelson DW, You JO, Phaneuf MD, LoGerfo FW, Pradhan-Nabzdyk L. Development of a composite electrospun polyethylene terephthalate-polyglycolic acid material: Potential use as a drug-eluting vascular graft. Journal of Nanomaterials Volume 2015 (2015), Article ID 340981, 7 pages.

Raof NA, Rajamani D, Chu HC, Gurav A, Johnson JM, LoGerfo FW, Bhasin M, Pradhan-Nabzdyk L. The effects of transfection reagent polyethyleneimine (PEI) and non-targeting control siRNAs on global gene expression in human aortic smooth muscle cells. BMC Genomics 2016;17(1):20. 

Tellechea A, Leal EC, Kafanas A, Auster ME, Kuchibhotla S, Ostrovsky Y, Tecilazich F, Baltzis D, Zheng Y, Carvalho E, Zabolotny JM, Weng Z, Petra A, Patel A, Panagiotidou S, Pradhan-Nabzdyk L, Theoharides TC, Veves A. Mast cells regulate wound healing in diabetes. Diabetes 2016;65(7):2006-19.

Bodewes T, Johnson J, Hyunh C, Muralidharan S, Contreras M, LoGerfo FW and 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. Acta Biomaterialia (under revision).