David Goukassian, MD, PhD
- PROFESSOR | Medicine, Cardiology
Research Topics:Aging, Angiogenesis, Anti-Tumor Therapy, Antibody Development, Atherosclerosis, Cancer, Cardiovascular, Chemokines, Cytokines, DNA Repair, Endothelial Cells, Epigenetics, Epigenomics, Fibrosis, Gene Regulation, Genetics, Genomics, Growth Factors and Receptors, Inflammation, Molecular Biology, Receptors, Regeneration, Space Flight, Technology & Innovation, Translational Research, Tumor Suppressor Genes, Tumorigenesis
Dr. David A. Goukassian is a graduate of Yerevan State Medical University, class of 1985. After practicing Medicine and Dermatology for four years at the Masis Regional Hospital he went to Moscow, Russia in 1989 for post-graduate courses and completed his Ph.D. at Central Advanced Training Institute for Physicians in 1992. Between 1992 - 1994 he was the Executive Medical Director of International project on development of “Elasticity Imaging for Early Diagnosis of Breast and Prostate Cancers” at the Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences. On the wings of this project Dr. Goukassian arrived to United States in 1994 where he continued leading the R&D division of this project. In 1996 he decided to further his career in biomedical research and accepted NIH-funded post-doctoral fellowship in the fields of Aging, Genetics and Biochemistry. In 1999 he became an Instructor of Dermatology, at Boston University School of Medicine, Department of Dermatology. In 2001 he accepted a second post-doctoral fellowship in the field of Stem and Progenitor Cell Biology at the Tufts University School of Medicine. Between 1999 - 2004 he was promoted to Assistant, then Associate Professor of Dermatology and Medicine at Boston University School of Medicine. In 2004 he also joined the faculty of Cardiovascular Research Division at Tufts University School of Medicine as Associate Professor of Medicine. He was appointed as the Director of Cardiovascular Research Center at Genesys Research Institute, at Steward St Elizabeth’s Medical Center in 2012- 2015, where he was leading several major projects in the fields of Cardiovascular Space Radiobiology, Cancer Therapeutics, Stem and Progenitor Cell Biology. He continued the Cardiovascular Space Radiobiology work while at Temple University School of Medicine 2016-2018. In late 2018 he joined Cardiovascular Research Institute at Icahn School of Medicine at Mount Sinai as Professor of Medicine/Cardiology.
Dr. Goukassian has a wide-range of expertise and experience that spans from molecular and cellular biology, age-associated decline in DNA damage and repair, as well as age-associated changes in cardiac repair and regeneration with specific emphasis on studies discerning signaling cascades in the context of cardiovascular disease knockout and transgenic mouse models that mimic aging phenotype. His research is aimed at development of novel therapies based on TNF-TNFR1/p55 and -TNFR2/p75 ligand-receptor interaction, specifically – (1) development of therapies to improve post-ischemic repair, regeneration and neovascularization processes; and (2) development of universal platform therapeutics to improve stem cell and gene therapy outcomes in damaged tissues.
His most recent research focus is the field of Cardiovascular Space Radiobiology, studying cardiovascular risks for development of countermeasures during and after long-duration deep space missions. These studies are focused on using integrated physiological approaches along with genomic, proteomic and epigenetic methodologies to understand molecular mechanisms of space radiation-induced long-term cardiovascular degenerative risks, development of mouse models for evaluation of space radiation-induced Excess Relative Risks (ERR), development of predictive biomarkers for estimation of ERR, development of countermeasures for NASA’s future long-duration space missions to Moon, near Earth asteroids and Mars. These studies have significant implications for NASA’s efforts to develop heart disease risk estimates for astronauts, as well as for prevention of radiation-induced cardiovascular diseases in cancer patients receiving conventional and particle radiotherapy.
Multi-Disciplinary Training AreasCancer Biology [CAB], Genetics and Data Science [GDS], Immunology [IMM], Pharmacology and Therapeutics Discovery [PTD]
MD, Yerevan Medical University
PhD, Central Advanced Training Institute for Physicians
Post-Doctoral Fellow, Boston University School of Medicine
Post-Doctoral, Tufts University School of Medicine
Development of novel anticancer therapeutics
Since 2011, Dr. Goukassian has been working on the development of novel anti-cancer treatment modalities based on inhibition of TNF signaling via selective blocking of one of its receptors (TNFR2 p75) for treatment of various human tumors including, but not limited to, lung, breast and melanoma. As result of this work we developed new monoclonal antibodies that block the pro-survival receptor of TNF. Our studies showed that when pro-survival TNF2 is blocked in the host (p75KO mice) or cancer cells themselves (knockdown TNFR2 in cancers cells with p75 shRNA) there is very significant inhibition of tumor angiogenesis and more than 50-60% reduction in tumor growth. What we also found is that an initial inhibition of TNFR2 induced the production and release of Tumor Necrosis Factor (death of cancer cells) into tumor tissue. Therefore, the TNF naturally released by dying tumor cells produce their “own poison” as long as TNFR2 is neutralized in the cells of tumor tissue. This approach offers paradigm changing cancer treatment targeting proliferative and silent cancer cells, cancer associated tumor stroma and endothelial cells providing an effective method of “priming the tumor for self-destruction”.
Stem and progenitor cell biology, therapeutic angiogenesis and tissue regeneration
Since 1998, the focus of Dr. Goukassian's research efforts has been on identifying the role of TNF in ischemia-induced inflammation, tissue regeneration, therapeutic angiogenesis and gene therapy. My research is aimed at development of treatments based on TNF-TNFR1/p55 and -TNFR2/p75 ligand-receptor interaction, specifically, (1) development of therapies to improve post-ischemic repair, regeneration and neovascularization processes; (2) development of universal platform therapeutics to improve stem cell and gene therapy outcomes in damaged tissues. TNF, a pro-inflammatory cytokine, is highly expressed in any damaged tissue, and plays a key role in the repair and regeneration processes via its two receptors, TNFR1 (p55) and TNFR2 (p75), whereby p55 mediates cytotoxic effects while p75 is pro-survival. Inflammation is an important phase of tissue regeneration processes. Perturbations in the spatial distribution of inflammatory cells, changes in the type and magnitude of the inflammatory infiltrate, disrupted temporal sequence, results in a persistent rather than resolved inflammatory phase and functional impairment of the damaged tissue. As a pro-inflammatory cytokine, TNF induces apoptosis and blocks stem and progenitor cell differentiation. The key finding of my research in this field with major therapeutic implications is that - restoration or overexpression of TNFR2/p75 (gene therapy) or inhibition of TNFR2/p55 (neutralizing antibody or small molecules) improves recovery in damaged tissue through inhibition of prolonged inflammation and cell death, promotion of therapeutic angiogenesis and development of new vascular network, thereby creating tissue environment for recruitment, incorporation and function of endogenous and exogenous stem cells and increasing survival of the resident differentiated cells and adult stem cells. This approach will improve stem and progenitor cell-therapy effectiveness and outcomes and could serve as a universal platform for stem cell and gene therapy.
Cardiovascular Space and Terrestrial Radiobiology
Dr Goukasian's earlier research evolved from formal training in DNA damage and repair, genetics and immunology, to a recent focus on using integrated physiological approaches along with genomic, proteomic and epigenetic methodologies to understand molecular mechanisms of space radiation-induced long-term cardiovascular degenerative risks, development of mouse models for evaluation of space radiation-induced Excess Relative Risks-ERR, development of predictive biomarkers for estimation of ERR, development of countermeasures for NASA’s future long-duration space missions to Moon, near Earth asteroids and Mars. Researched cardiovascular disease risks for astronauts from low dose radiation exposures. Assisted NASA in developing heart disease risk estimates and proposed measures to prevent Earth-bound population from radiation-induced cardiovascular diseases in cancer patients receiving “standard of care” conventional and particle radiotherapy. We found, that low dose exposures of charged particles present in the space IR environment may have significant impact on CV and bone marrow system. These studies have significant implications for NASA’s efforts to develop heart disease risk estimates for astronauts, as well as for prevention of radiation-induced cardiovascular diseases in cancer patients receiving conventional and particle radiotherapy.
Garikipati VN, Verma SK, Cheng Z, Liang D, Truongcao MM, Cimini M, Yue Y, Huang G, Wang C, Benedict C, Tang Y, Mallaredy V, Ibetti J, Grisanti L, Schumacher SM, Gao E, Rajan S, Wilusz JE, Goukassian D, Houser SR, Koch WJ, Kishore R. Circular RNA CircFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis. Nature communications 2019 09; 10(1).
Sano S, Oshima K, Wang Y, MacLauchlan S, Katanasaka Y, Sano M, Zuriaga MA, Yoshiyama M, Goukassian D, Cooper MA, Fuster JJ, Walsh K. Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome. Journal of the American College of Cardiology 2018 02; 71(8).
Cimini M, Garikipati VN, de Lucia C, Cheng Z, Wang C, Truongcao MM, Lucchese AM, Roy R, Benedict C, Goukassian DA, Koch WJ, Kishore R. Podoplanin neutralization improves cardiac remodeling and function after acute myocardial infarction. JCI insight 2019 07; 5.
Sasi SP, Yan X, Zuriaga-Herrero M, Gee H, Lee J, Mehrzad R, Song J, Onufrak J, Morgan J, Enderling H, Walsh K, Kishore R, Goukassian DA. Different Sequences of Fractionated Low-Dose Proton and Single Iron-Radiation-Induced Divergent Biological Responses in the Heart. Radiation research 2017 08; 188(2).
Yue Y, Garikipati VN, Verma SK, Goukassian DA, Kishore R. Interleukin-10 Deficiency Impairs Reparative Properties of Bone Marrow-Derived Endothelial Progenitor Cell Exosomes. Tissue engineering. Part A 2017 11; 23(21-22).
Garikipati VN, Verma SK, Jolardarashi D, Cheng Z, Ibetti J, Cimini M, Tang Y, Khan M, Yue Y, Benedict C, Nickoloff E, Truongcao MM, Gao E, Krishnamurthy P, Goukassian DA, Koch WJ, Kishore R. Therapeutic inhibition of miR-375 attenuates post-myocardial infarction inflammatory response and left ventricular dysfunction via PDK-1-AKT signalling axis. Cardiovascular research 2017 Jul; 113(8).
Sasi SP, Song J, Park D, Enderling H, McDonald JT, Gee H, Garrity B, Shtifman A, Yan X, Walsh K, Natarajan M, Kishore R, Goukassian DA. TNF-TNFR2/p75 signaling inhibits early and increases delayed nontargeted effects in bone marrow-derived endothelial progenitor cells. The Journal of biological chemistry 2015 Nov; 290(45).
Muralidharan S, Sasi SP, Zuriaga MA, Hirschi KK, Porada CD, Coleman MA, Walsh KX, Yan X, Goukassian DA. Ionizing Particle Radiation as a Modulator of Endogenous Bone Marrow Cell Reprogramming: Implications for Hematological Cancers. Frontiers in oncology 2015; 5.
Coleman MA, Sasi SP, Onufrak J, Natarajan M, Manickam K, Schwab J, Muralidharan S, Peterson LE, Alekseyev YO, Yan X, Goukassian DA. Low-dose radiation affects cardiac physiology: gene networks and molecular signaling in cardiomyocytes. American journal of physiology. Heart and circulatory physiology 2015 Dec; 309(11).
Sasi SP, Park D, Muralidharan S, Wage J, Kiladjian A, Onufrak J, Enderling H, Yan X, Goukassian DA. Particle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells. Stem cells international 2015; 2015.
Sasi SP, Rahimi L, Yan X, Silver M, Qin G, Losordo DW, Kishore R, Goukassian DA. Genetic deletion of TNFR2 augments inflammatory response and blunts satellite-cell-mediated recovery response in a hind limb ischemia model. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2015 Apr; 29(4).
Yan X, Sasi SP, Gee H, Lee J, Yang Y, Mehrzad R, Onufrak J, Song J, Enderling H, Agarwal A, Rahimi L, Morgan J, Wilson PF, Carrozza J, Walsh K, Kishore R, Goukassian DA. Cardiovascular risks associated with low dose ionizing particle radiation. PloS one 2014; 9(10).
Sasi SP, Song J, Park D, Enderling H, McDonald JT, Gee H, Garrity B, Shtifman A, Yan X, Walsh K, Natarajan M, Kishore R, Goukassian DA. TNF-TNFR2/p75 signaling inhibits early and increases delayed nontargeted effects in bone marrow-derived endothelial progenitor cells. The Journal of biological chemistry 2014 May; 289(20).
Sasi SP, Bae S, Song J, Perepletchikov A, Schneider D, Carrozza J, Yan X, Kishore R, Enderling H, Goukassian DA. Therapeutic non-toxic doses of TNF induce significant regression in TNFR2-p75 knockdown Lewis lung carcinoma tumor implants. PloS one 2014; 9(3).
Shtifman A, Pezone MJ, Sasi SP, Agarwal A, Gee H, Song J, Perepletchikov A, Yan X, Kishore R, Goukassian DA. Divergent modification of low-dose ⁵⁶Fe-particle and proton radiation on skeletal muscle. Radiation research 2013 Nov; 180(5).
Goukassian DA, Sharov A, Rhodes J, Coleman C, Eller MS, Sharova T, Bhawan J, Gilchrest BA. Topical application of thymidine dinucleotide to newborn mice reduces and delays development of UV-induced melanomas. The Journal of investigative dermatology 2012 Nov; 132(11).
Sasi SP, Yan X, Enderling H, Park D, Gilbert HY, Curry C, Coleman C, Hlatky L, Qin G, Kishore R, Goukassian DA. Breaking the 'harmony' of TNF-α signaling for cancer treatment. Oncogene 2012 Sep; 31(37).
Kishore R, Tkebuchava T, Sasi SP, Silver M, Gilbert HY, Yoon YS, Park HY, Thorne T, Losordo DW, Goukassian DA. Tumor necrosis factor-α signaling via TNFR1/p55 is deleterious whereas TNFR2/p75 signaling is protective in adult infarct myocardium. Advances in experimental medicine and biology 2011; 691.
Coleman C, Levine D, Kishore R, Qin G, Thorne T, Lambers E, Sasi SP, Yaar M, Gilchrest BA, Goukassian DA. Inhibition of melanoma angiogenesis by telomere homolog oligonucleotides. Journal of oncology 2010; 2010.
Zattra E, Coleman C, Arad S, Helms E, Levine D, Bord E, Guillaume A, El-Hajahmad M, Zwart E, van Steeg H, Gonzalez S, Kishore R, Goukassian DA. Polypodium leucotomos extract decreases UV-induced Cox-2 expression and inflammation, enhances DNA repair, and decreases mutagenesis in hairless mice. The American journal of pathology 2009 Nov; 175(5).
Arad S, Zattra E, Hebert J, Epstein EH, Goukassian DA, Gilchrest BA. Topical thymidine dinucleotide treatment reduces development of ultraviolet-induced basal cell carcinoma in Ptch-1+/- mice. The American journal of pathology 2008 May; 172(5).
Goukassian DA, Qin G, Dolan C, Murayama T, Silver M, Curry C, Eaton E, Luedemann C, Ma H, Asahara T, Zak V, Mehta S, Burg A, Thorne T, Kishore R, Losordo DW. Tumor necrosis factor-alpha receptor p75 is required in ischemia-induced neovascularization. Circulation 2007 Feb; 115(6).
Marwaha V, Chen YH, Helms E, Arad S, Inoue H, Bord E, Kishore R, Sarkissian RD, Gilchrest BA, Goukassian DA. T-oligo treatment decreases constitutive and UVB-induced COX-2 levels through p53- and NFkappaB-dependent repression of the COX-2 promoter. The Journal of biological chemistry 2005 Sep; 280(37).
Goukassian DA, Gilchrest BA. The interdependence of skin aging, skin cancer, and DNA repair capacity: a novel perspective with therapeutic implications. Rejuvenation research 2004; 7(3).
Goukassian DA, Helms E, van Steeg H, van Oostrom C, Bhawan J, Gilchrest BA. Topical DNA oligonucleotide therapy reduces UV-induced mutations and photocarcinogenesis in hairless mice. Proceedings of the National Academy of Sciences of the United States of America 2004 Mar; 101(11).
Goukassian DA, Kishore R, Krasinski K, Dolan C, Luedemann C, Yoon YS, Kearney M, Hanley A, Ma H, Asahara T, Isner JM, Losordo DW. Engineering the response to vascular injury: divergent effects of deregulated E2F1 expression on vascular smooth muscle cells and endothelial cells result in endothelial recovery and inhibition of neointimal growth. Circulation research 2003 Jul; 93(2).
Goukassian DA, Bagheri S, el-Keeb L, Eller MS, Gilchrest BA. DNA oligonucleotide treatment corrects the age-associated decline in DNA repair capacity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2002 May; 16(7).
Goukassian D, Díez-Juan A, Asahara T, Schratzberger P, Silver M, Murayama T, Isner JM, Andrés V. Overexpression of p27(Kip1) by doxycycline-regulated adenoviral vectors inhibits endothelial cell proliferation and migration and impairs angiogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2001 Sep; 15(11).
Goukassian D, Sanz-González SM, Pérez-Roger I, Font de Mora J, Ureña J, Andrés V. Inhibition of the cyclin D1/E2F pathway by PCA-4230, a potent repressor of cellular proliferation. British journal of pharmacology 2001 Apr; 132(7).
Goukassian D, Gad F, Yaar M, Eller MS, Nehal US, Gilchrest BA. Mechanisms and implications of the age-associated decrease in DNA repair capacity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2000 Jul; 14(10).