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Michael P. Murphy, MD

Associate Professor of Surgery
Associate Professor of Cellular and Integrative Physiology Clinical
Director, Vascular and Cardiac Center for Adult Stem Cell Therapy
Director, IU Center for Aortic Disease

Specialty: Vascular Surgery
Medical School: Columbia University
Residency: Brigham and Women's Hospital, Harvard Medical School
Fellowship: Duke University (Vascular Surgery)

 

Dr. Murphy is a native of New York and received his medical degree from the College of Physicians and Surgeons of Columbia University where he was selected for Alpha Omega Alpha honor medical society during his junior year. Dr. Murphy completed his general surgery training at the Brigham and Women’s Hospital, Harvard Medical School where he was chosen for the Francis Daniels Moore Senior Resident Award. During his residency he spent two years in research in the cardiac surgery laboratory at the Harvard Medical School studying heart failure and skeletal muscle augmentation of ventricular function. Dr. Murphy continued on as faculty as the Assistant to the Surgeon in Chief at the Brigham and Women’s Hospital and Instructor in Surgery at Harvard Medical School before continuing his fellowship training in vascular surgery at Duke University Medical Center. Dr. Murphy joined the faculty of the Indiana University School of Medicine in 2005 where he serves as Associate Professor of Surgery and Cellular and Integrative Physiology (tenured in research), Clinical Director for the Vascular and Cardiac Adult Stem Cell Therapy Center, Director of the IU Center for Aortic Disease, and Executive Committee of the Cardiovascular Cell Therapy Research Network for the National Heart, Lung, and Blood Institute.

 

Dr. Murphy’s interest is in stem cell physiology and he designed and conducted the first clinical trial in the U.S. using autologous bone marrow cells for peripheral arterial disease in 2003. Dr. Murphy has multiple grants from the National Institutes of Health, the Veterans Administration, and the Strategic Research Initiatives including a $63 million program grant (NIH 1UM1HL113457-01) that is focusing on clinical research in stem cell therapies for cardiovascular disease. Dr. Murphy has authored over sixty publications and is currently the national Principal Investigator on four stem cell trials in arterial and aortic disease. He serves as Director of the IU Health Center for Aortic Disease and Clinical Director the Vascular and Cardiac Adult Stem Cell Therapy Center.

 

Dr. Murphy belongs to the American Medical Association, American College of Surgeons, American Heart Association, International Society for Stem Cell Research, North American Vascular Biology Organization, American Society of Gene and Cell Therapy, International Society for Stem Cell Research, Society for Vascular Surgery, and Association for Academic Surgery.

 

Dr. Murphy joined the U.S. Army Reserve in 2004 and served two tours in Iraq as a vascular and trauma surgeon, receiving the Army Commendation Medal, Meritorious Service Medal, and Bronze Star for his service. He now resides in Carmel, Indiana with his wife, Laura, and their family.

Affiliations

Riley Physicians
IU Health Physicians

Hospitals

IU Health Methodist/IU Health University
IU Health North
IU Health Saxony

Location Information

Richard L. Roudebush VA Hospital

1481 W. 10th St.

Indianapolis, IN 46202


IU Health Multi-Specialty Clinic

1801 N. Senate Blvd., Ste 3500

Indianapolis, IN 46202


Clinical Interests

Array


Accepting New Patients

Schedule an Appointment  Clinical Trials

I. Murphy Laboratory and Clinical Research Team

 

 

Role

Project

Clifford Babbey, BS

Director of Operations

 

Sunil Tholpady,MD,PhD

Investigator

Microvascular network formation, induced pluripotent stem cells, biomatrices, tissue ischemia

 

Linden Green. PhD

 

Investigator

 

Autoimmune mechanisms in AAA, T regulatory cell physiology,

 

Praveen Kusumanchi, PhD

 

Investigator

 

Genetic modification of MSCs, tissue ischemia, nanoparticle development

 

Lili Zhang, BA

 

Research Technician

 

All

 

Keisin Wang, MD

 

Research Fellow

 

Synergy of T regulatory and Tr1 cells in AAA suppression, lymphatic directed immune therapy.

 

Kristen Wanczyk, RN

 

Study Coordinator

 

CHAMP Trial, MOBILE Continued Access, MSC induction of Treg in AAA Trial

 

Toni Lathrop, RN

 

Study Coordinator

 

CHAMP Trial, MOBILE Continued Access, MSC induction of Treg in AAA Trial

 

 

II. Current Funding. 

 

NIH 1UM1HL113457-01 .Utility of Autologous and Allogeneic Cell Therapy for Peripheral Arterial Disease. Cardiovascular Cell Therapy Research Network (CCTRN) of the National Heart, Lung, and Blood Institute.. Murphy, PI. Begin Date: 3/5/2012. End Date: 2/28/19.

R01HL128827-01 (NHLBI), A clinical and histological analysis of mesenchymal stem cells.  Begin Date: 6/1/2016. End Date: 3/31/2020. Murphy, PI.

1I01CX001407-01A1 (VA Clinical Research and Development Award). Mesenchymal stem cells induce regulatory T cells in patients with aortic aneurysm.. Begin Date: 7/1/2016. End Date: 3/31/2020. Murphy, PI.

1IS1BX003116-01A1. (VA Office of Research and Development  Shared Equipment Program) 3DBioFactory Bioprinter, regenHU Biosystem Architects. Begin Date: 6/1/2016..

A Phase I study to examine the safety and efficacy of the MarrowStim P.A.D. Kit in concentrating autologous bone marrow cells for the prevention of wound complications in below-knee amputation. This is a randomized, open label, placebo controlled trial that will enroll twenty patients undergoing below knee amputation.(Zimmer-Biomet) Begin Date: March 1, 2016.  Murphy, PI.

Biorepository and Ancillary Studies for MOBILE continuing access. We will operate the collection and preservation of blood and bone marrow specimens from patients enrolled in the continuing access for future genetic, molecular, and cellular analyses.( Zimmer-Biomet). Murphy, PI. Begin Date: October 1, 2015.

Center of Excellence in Cardiovascular Research. NIH Clinical and Translational Sciences Institute. A clinical and histological analysis of mesenchymal stem cells in amputations.. Murphy PI. Begin Date: 10/1/15.

Veterans Directorship Award. The Richard Roudebush Veterans Administration Medical Center. Support to develop translational programs emphasizing the genetic, molecular, and cellular mechanisms in the pathogenesis of aneurysmal degeneration of the aorta and novel therapies for treatment. Murphy, PI. Begin Date: 11/ 1/13. End Date: 12/31/18.

 Strategic Research Initiatives Grant. The IU Health Center for Aortic Disease. Institutional program grant. $200K. Murphy, PI. Awarded $200K November 12, 2013. Renewable June1, 2014-2018.

Biomet, Inc. The MOBILE Trial: MarrowStim (TM) PAD kit for the treatment of critical limb ischemia (CLI) in subjects with severe peripheral arterial disease (PAD). Multicenter Phase III randomized, double blinded trial. , Murphy, National PI. End: July 1, 2016.

 

III. Current Projects.

 

A.  Angiogenic and Vasculogenic Approaches to Tissue Ischemia (Preclinical). This is a series of projects designed with the objective of advancing therapeutic approaches to improving limb perfusion using combinations of vasculogenic cells and biomatrices.

 

  1. Defining the mechanisms of autologous concentrated bone marrow aspirate (cBMA )mediated angiogenesis. Using our mouse hindlimb ischemia model we are defining the mechanisms by which concentrated bone marrow aspirate improves tissue perfusion by quantifying capillary formation, gene, and cytokine expression profiles, and laser Doppler perfusion. Our working hypothesis is that the angiogenic potential of cBMA is dependent upon the number of CD133+CD34+CD45+CD16-CD14-CD235-  Proangiogenic Hematopoietic Cells. This data will be used to support our final manuscript for the MOBILE Phase III Trial and provide preliminary data to support a NIH or VA Cooperative Studies grant for a Phase II trial assessing cBMA in claudicants. Funded by Zimmer-Biomet.
  2. Synergistic effect of mesenchymal stromal cells and ECFCs in forming functional microvascular networks in vivo.  This project expands upon our original description of synergy in vascular network formation between MSCs and ECFCs in collagen-fibronectin plugs in mice. Here we will inject variations of mouse and human MSCs with ECFCs isolated from human greater saphenous vein, umbilical cord blood, and human iPSC ECFCs embedded in alginate hydrogel (currently being used clinically) and a polymerizerable collagen matrix that solidifies at body temperature developed by one of our collaborators at Purdue (Hardin). The cell mixture we be injected from the point of femoral artery ligation to the point where the popliteal artery reconstitutes in the mouse hindlimb to determine if we can create a vascular network that bridges these points. The long term objective is to bring this concept to a pilot trial in patients with CLI that have tibial-peroneal occlusive disease. This program is funded by the VA Director’s Award.

 

B.  Cell Therapy for Cardiovascular Disease (Clinical).

 

  1. Cardiovascular Cell Therapy Research Network of the NHLBI (NIH 5UM1HL113457-04)(Murphy,PI). Enrollment in the PACE Phase II trial has been completed and our center was the leading recruiter for this study within the network. We are participating in ancillary studies through the Biorespository and plan to begin CONCERT-CHF and SENECA  trial in heart failure in May, 2016.
  2. MOBILE Phase III Clinical Trial (Murphy, National PI). This a 30 center, randomized, double blinded clinical trial, the first pivotal cell therapy trial in the U.S. This is a trial that I designed and received FDA approval for in 2004 and brought through Phase I, II, and now III as the national PI. We completed enrollment of 152 patients in  May, 2015, follow up will be completed May, 2016 and expect to produce the final plenary report of the outcomes in October 2016.This trial was funded by Zimmer-Biomet, Warsaw, IN.
  3. MOBILE Continuing Access Program. I am leading a non-randomized registry that is a continuation of the MOBILE Trial at 20 sites in the US. Zimmer-Biomet is funding ancillary studies using flow cytometry, mass spectroscopy, gene arrays, and BOLD MRI to delineate the mechanistic effects of cBMA in patients with CLI. Zimmer-Biomet is funding creation of a biorepository that I will direct and which will collect bone marrow and blood specimens from enrolled patients. These samples will be made available to investigators through the Vascular Research Initiatives program through the Society of Vascular Surgery.
  4. A Clinical and Histological Analysis of MSCs in Amputations (1R01HL128827-01) (Murphy ,PI). This is a Phase I trial with two distinct objectives.  The first objective is to assess the ability of allogeneic MSCs in preventing ischemic wound complications after semi-elective below knee amputation due to limb ischemia and prevent conversion from below knee to above knee amputation. The second objective is to provide a first in man genetic, proteomic, and functional analysis of gender mismatched HLA-A2+ MSCs injected at four sites in the anterior tibialis muscle below the point of amputation. After MSC injection in the thigh and the AT muscle patients will be randomized to BKA at Day 3, 7, 14, and 21 post-injection. This program is funded by the Center of Excellence in Cardiovascular Research through the Clinical and Translational Sciences Institute at IU and we are awaiting a council decision regarding our recent R-01 that received a 10% score. In addition, Zimmer-Biomet is funding an identical trial using their cBMA product (MarrowStim) in twenty patients undergoing BKA. Our future plans are to continue this study to a Phase II multi-center trial focusing on wound healing after BKA through the NIH, use alginate hydrogel with MSCs and ECFCs in in the AT muscle , and use the preliminary safety data for FDA approval to use HLA matched iPSC ECFCs in the AT Muscle in this model. I am currently working with Waisman Biomanufacturing at the University of Wisconsin to use their FDA approved stock of human IPSCs from which we will derive ECFCs in a GMP lab. This is the theme of a R-01 grant scheduled for June, 2016.

 

C. Innate and Adaptive Immune Responses in the Pathogenesis of Abdominal Aortic Aneurysm. Our central hypothesis is that the chronic inflammatory process that characterizes AAA initiation and progression is a result of memory T cell sensitization to epitopes produced by lung injury from cigarette exposure. It is when regulatory control is lost that these effector T cells react to similar epitopes (elastin and collagen fragments) in the aortic wall. The infra-renal aorta is uniquely affected as it contains the fewest number of smooth muscle cells and elastin lamellae and is exposed to unique transmural pressure forces due aortic luminal tapering and bifurcation of the common iliac arteries. We believe that T cell subsets initiate this cascade that leads to destruction of mural integrity early and aneurysm expansion is then driven by transmural forces. Thus our approach for interrupting this process is by targeting regulatory T-cells in patients with small AAA (35-45 mm).

 

  1. Dysregulation of Innate and Adaptive Immune Responses in Patients with AAA. We and others have demonstrated that natural T-regulatory (CD25+FoxP3+) are diminished in number and immune suppressor function. Most recently we have demonstrated that CD4+CD49b+LAG-3+ Tr1 cells are diminished in number, a pivotal discovery that supports our central hypothesis. Concurrently we have discovered that patients with diminished Tr1 cells also have significantly decreased serum levels of IL-10. Consequently our experiments are focusing in epigenetic events that interfere with IL-10 synthesis (miRNA27a), disruption of the JNK/STAT3 signaling pathways, and characterization of peripheral dendritic IL-10 cells. This is the theme for an R-21 being submitted this June cycle.
  2. Mesenchymal Stromal Cell Modulation of Immune Responses in Suppression of AAA in a murine elastase model. Based on our discovery that maternally derived MSCs were in immediate juxtaposition to fetal derived endothelial cells in the chorionic villi of term placenta and highly immunosuppressive we used these MSCs in a murine model of AAA with colleagues at the Univ. of Virginia. More recently we have found the human MSCs robustly secrete IL-10 in a murine mouse AAA model and induce formation of murine T-reg and Tr1 cells. Ablation of Treg cells significantly decreased subsequent formation of Tr1 cells. Defining the cross talk between MSCs, Tergs, and Tr1 cells is the theme of a R21 submitted by Linden Green currently under review.
  3. T-regulatory cell suppression of AAA. Based on the preliminary data that we have obtained demonstrating that natural FoxP3+ Tregs induced by MSCs may initiate a downstream anti-inflammatory cascade that includes IL-10 secreting Tr1 cells as well as myeloid derived suppressor cells we are exploring the efficacy of Tregs alone (human Tregs from the Interdisciplinary Stem Cell Institute at Univ. of Miami, murine Tregs, and human umbilical cord derived Tregs) and in combination with MSCs.
  4. Lymphatic Directed Immune Therapy to Suppress AAA. My laboratory has found that injection of MSCs into the psoas muscles of our mouse AAA model is superior  to intra-venous delivery in increasing serum human IL-10 levels, murine Tr1 cells, and decreasing the severity of AAA. We have discovered that IM injection into the psoas muscle increased human MSC engraftment and human IL-10 levels in the peri-aortic nodes and consequently increased intra-nodal Tr1 cells. Our hypothesis is that local concentration of MSC derived IL-10 in the lymph nodes is critical at the time antigen presenting cells engage naïve CD4+ T-cells, shifting the direction of polarization from a  T effector cell to an antigen specific immunosuppressive Tr1 cell. We are submitting a R21 that will explore the efficacy of psoas muscle deliver to inguinal node injection of MSCs (Aim 1); and Aim 2, test the feasibility of CD4+ targeted nanoparticle delivery of IL-10 via the best route identified in Aim 1.
  5. Collagen biomatrix to arrest AAA expansion. Using the  collagen polymer developed by Sherry Hardin,PhD and with Craig Goergen,PhD we are exploring the potential of translumbar injection under ultrasound guidance of this matrix in the  peri-aortic space, with and without MSCs and IL-10, in attenuating aneurysm severity in the angiotensin Apo E-/- model.
  6. Efficacy of escalating doses of allogenic MSCs in inducing FoxP3+ T-regulatory and Tr1 cells in patients with AAA (1I01CX001407-01A1 CSR&D Merit Review Award). This is a randomized, blinded Phase I trial designed to determine the most effective MSC dose delivered IV in promoting FoxP3+ Tregs (primary endpoint), serum levels of IL-10, and suppressing aortic inflammation as measured by 18-FDG uptake on PET/CT.
  1. Miller SJ, Norton LE, Murphy MP, Dalsing MC, Unthank JL. The role of the renin-angiotensin system  and oxidative stress in spontaneously hypertensive rat  mesenteric collateral growth impairment. Am J Physiol Heart Circ Physiol.2007;292: H2523-H2531.
  2. Murphy MP, Wang H, Patel AN,  Kambhampati S, Angle N,Chan K, Marleau AM, Pyszniak A, Carrier E, Ichim TE, Riordan NH. Allogeneic endometrial regenerative cells: an "off the shelf" solution for critical limb ischemia? Journal of Translational Medicine 2008.
  3. Zhang Y, Ingram DA, Murphy MP, Saadatzadeh MR, Mead LR, Prater DN, Rehman J. Release of proinflammatory mediators and expression of proinflammatory adhesion molecules by endothelial progenitor cells. Am J Physiol Heart Circ Physiol 2009;296: H103-111.
  4. Distasi MR, Case J, Murphy MP, Ziegler MA, Dinauer MC, Yoder MC, Haneline LS, Dalsing MC, Miller SJ, Labarrere CA, Ingram DA, Unthank JL. Suppressed hindlimb perfusion in Rac2–/– and Nox2–/– mice does not result from impaired collateral growth. Am J Physiol Heart Circ Physiol 2009;296: H877-H886.
  5. Traktuev DO, Prater DN, Merfeld-Clauss S, Sanjeevaiah AR, Murphy MP, M. Reza Saadatzadeh MR, Johnstone BH, Ingram DA, March KL. Robust Functional Vascular Network Formation In Vivo by Cooperation of Adipose Progenitor and Endothelial Cells. Circ Res 2009;104:1410-1420.
  6. Zhong Z, Patel AN, Ichim TE, Riordan NH, Wang H, Min WP, Woods EJ, Reid M, Mansilla E, Marin GH, Drago H, Murphy MP, Minev B. Feasibility investigation of allogeneic endometrial regenerative cells. J Transl Med. 2009 Feb 20;7:15.
  7. Eitel JA, Bijangi-Vishehsaraei K, Saadatzadeh MR, Bhavsar JR, Murphy MP, Pollok KE, Mayo LD. PTEN and p53 are required for hypoxia induced expression of maspin in glioblastoma cells. Cell Cycle. 2009 Mar 15; 8(6):896-901.
  8. Estes ML, Mund JA, Mead LE, Prater DN, Cai S, Wang H, Pollok KE, Murphy MP, An CS, Srour EF, Ingram DA, Case J. Application of polychromatic flow cytometry to identify novel subsets of circulating cells with angiogenic potential. Cytometry.
  9. Riordan NH, Ichim TE, Min WP, Wang H, Solano F, Lara F, Alfaro M, Rodriguez JP, Harman RJ, Patel AN, Murphy MP, Lee RR, Minev B. Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Transl Med. 2009 Apr 24;7:29. Review.
  10. Mikirova NA, Jackson JA, Hunninghake R, Kenyon J, Chan KW, Swindlehurst CA, Minev B, Patel AN, Murphy MP, Smith L, Alexandrescu DT, Ichim TE, Riordan NH. Circulating endothelial progenitor cells: a new approach to anti-aging medicine. J Transl Med. 2009 Dec 15;7:106. Review.
  11. Ichim TE, Solano F, Lara F, Rodriguez JP, Cristea O, Minev B, Ramos F, Woods EJ, Murphy MP, Alexandrescu DT, Patel AN, Riordan NH. Combination stem cell therapy for heart failure. Int Arch Med. 2010 Apr 14;3(1):5.
  12. Ziegler MA, Distasi MR, Bills RG, Miller SJ, Alloosh M, Murphy MP, George Akingba A, Sturek M, Dalsing MC, Unthank JL.Marvels, mysteries, and misconceptions of vascular compensation to peripheral artery occlusion. Microcirculation. 2010 Jan;17(1):3-20. Review.
  13. Mikirova NA, Jackson JA, Hunninghake R, Kenyon J, Chan KW, Swindlehurst CA, Minev B, Patel AN, Murphy MP, Smith L, Ramos F, Ichim TE, Riordan NH. Nutraceutical augmentation of  circulating endothelial progenitor cells and hemaotopietic stem cells in human subjects. J Transl Med. 2010 Apr 8; 8:34.
  14. Bijangi-Vishehsaraei K*, Saadatzadeh M.R.*, Huang S, Murphy MP, and Safa AR. 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH) targets mRNA of the c-FLIP variants and induces apoptosis in MCF-7 human breast cancer cells. Mol Cell Biochem 2010.
  15. Murphy MP, Dalsing MC, Lawson JH, Shafique SS, Klein JH, McKale JM, Abonour RF,Hutchins GD, March KL. Autologous Bone Marrow Mononuclear Cell Therapy is Safe and Promotes Amputation Free Survival in Patients with Critical Limb Ischemia J Vasc Surg 2011;53:1565-74.
  16. Matos J, Fajardo A, Rapp BM, Dalsing MC, Motaganahalli RL, Akingba GA, Lemmon GW, Murphy MP. Evidence for Non-operative Management of Acute Limb Ischemia in the Infant. J Vasc Surg. 2011;55:1156-59.
  17. Rapp BM, Saadatzadeh RM, Tempel,ZS , Bhasvar J, Ofstein RH, Morone PM, Traktuev DO, Grimes B, March KL, Murphy MP.  Resident Endothelial Progenitor Cells from Human Placenta Have Greater Vasculogenic Potential than Circulating Endothelial Progenitor Cells from Umbilical Cord Blood.Cell Transplantation. 2011.
  18. Jester AL, Motaganahalli RL, Rapp BM, Akingba GA, Dalsing MC, Wilson MG, Fajardo A, Murphy MP. Autologous Bone Marrow Mononuclear Cell Therapy Produces Durable Benefits in Limb Salvage at Five Years Post-Treatment  J Vasc Surg 2011;54: 1542-45.
  19. Motaganahalli RL, Murphy MP, Sawchuck AP, Lemmon GL, Fajardo A, Akingba GA, Feliciano B, Cikrit DC, Richardson CR, Dalsing MC. Door To Treatment Time - Identifying Opportunities for Process Improvement: Results From an Institution Based Protocol Caring for Patients with Ruptured Aortic Aneurysms. J Vasc Surg, 2011; 53, 5S-6S.
  20. Rodriguez JP, Murphy MP, Hong S, Madrigal M, March KL, Minev B, Harman RJ, Chen CS, Timmons RB, Marleau AM, Riordan NH. Autologous stromal vascular fraction therapy for rheumatoid arthritis: rationale and clinical safety. Int Arch Med .2012 Feb 8; 5:5. doi: 10.1186/1755-7682-5-5.
  21. Sharma AK, Lu G, Jester A, Johnston W, Zhao Y, Hajzus V, Saadatzadeh MR, Su G, Bhamidipati CM, Mehta G, Kron IL, Laubach VE, Murphy MP, and Upchurch GR. Experimental abdominal aortic aneurysm formation is mediated by IL-17 and attenuated by mesenchymal stem cell treatment. Circulation 2012;126: S38-S45.
  22. Mizer JC, Ichim TE, Alexandrescu DT, Dasanu CA, Ramos F, Turner A, Woods EJ, Bogin V, Murphy MP, Koos D, Patel AN. Exogenous endothelial cells as accelerators of hematopoietic reconstitution. J Transl Med. 2012 Nov 21;10 (1):231.
  23. Perin EC, Willerson JT, Pepine CJ, Murphy MP, et al.. Phase II clinical research design in cardiology: learning the right lessons too well: observations and recommendations from the Cardiovascular Cell Therapy Research Network (CCTRN). Circulation 2012 000779R1.

Department of Surgery | 545 Barnhill Drive, Emerson Hall 203, Indianapolis, In 46202 | Phone: (317) 274-5771