UCR

Cell Biology and Neuroscience



Manuela Martins-Green


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Phone: (951) 827-2585
Fax: (951) 827-4286
Office Location: 2117 Biological Sciences
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Email: manuela.martins@ucr.edu

Manuela Martins-Green

Professor of Cell Biology
PhD, University of California, Davis, 1987

Biography

Research Program

My research program focuses on understanding the cell and molecular mechanisms involved in wound healing and tumorigenesis.  The work in my laboratory has four foci:

       1)   Wound Healing.

             A.  Normal Processes.  In the early stages of my career, I pioneered investigation of the role of chemokines in wound healing.  A recent search through the Web of Science on publications involving Chemokines and Wound Healing places UCR on top of all other institutions and me as the top investigator in the field.  Chemokines are small, secreted, stress-response cytokines that are highly conserved among higher vertebrates and are now known to be important in inflammatory diseases, viral infections (e.g. HIV), fibrosis and tumorigenesis.  As my program has developed, I have concentrated on activation, expression, function and mode of action of chemokines in healing, using animal models and complex human cultures (see #2 below).  Our studies have focused on the chemokine, Interleukine-8 (IL-8), what agents at the wound site stimulate its expression, the signal-transduction mechanisms by which this expression occurs, and what functions IL-8 performs during the healing process.  Our goals are to: (a) Identify commonalities in the signal transduction and transcription activation mechanisms that may lead the way to regulating the expression of chemokines for potential medical applications; (b) test the effects of IL-8 on the principal cellular components of the granulation tissue of wounds -- fibroblasts, myofibroblasts, endothelial cells, keratinocytes and immune cells - accompanied by tests directly to wounds; (c) characterize the function of IL-8 receptor(s) during wound healing.  To aid in these studies we have developed a transgenic humanized mouse model in which human CXCR1 is expressed in all tissues but can be activated in specific tissue by crossing with specific Cre mice.  These mice now have both CXCR1 and CXCR2 receptors and can therefore be used to study all of the effects of human IL-8 in vivo, something that was not possible before because a functional CXCR1 receptor has not been found in mice.

             B.  Impaired healing. I have focused on the effects of environmental toxicants, especially those present in cigarette smoke. We investigate the effects of (primarily) second-hand smoke on: (a) the development of atherosclerotic plaques (a form of impaired healing of blood vessels); (b) skin wound healing; (c) cornea epithelial wound healing. I am particularly interested in how chemokines are involved in these processes. Our aim here is to identify key processes affected by cigarette smoke and which chemicals in the smoke cause those effects. The extreme complexity of cigarette smoke has frustrated efforts to identify critical harmful components. We have now established a mouse model that mimics the common human conditions that lead to atherogenesis. We are using this model and are developing a human assay system (see #2) to identify the smoke components (or groups of components) responsible for initiation of atherosclerotic plaque formation. More recently, we have developed a chronic wound model using genetic manipulations which lead to delayed wound healing and when infection ensues leads to a chronic wound.

              C.  Bench to bedside.  We are using multiple factors to treat wounds in a time- and concentration-dependent manner to discover combinations that not only improve healing but also the regenerative capacity of the tissue. We are particularly interested in developing treatments for large burns. Through collaborations, we are developing matrices that are biocompatible, can be applied in large areas, and are biodegradable -- either naturally or by applying an enzyme.

2)   Engineering of human tissues.  In order to test the relevance for human biology of some of the hypotheses we have developed in animal systems, we are developing complex tissue cultures using primary human cells. We have already developed a novel human "skin" organ culture that we are now using to study some of the fundamental cell and molecular processes in normal and abnormal healing. We have also developed a system that allows us to test the effects of inflammatory agents on endothelial/epithelial permeability and we are currently developing an arterial wall model system for studies of atherogenesis induced by first- and second-hand cigarette smoke.  

 3)   Role of chemokines in development and progression of prostate cancer.  We are currently studying the effects of Pomegranate Juice (PJ) on various chemokine/chemokine receptor axes in prostate cancer progression. For this we are employing a multi-prong approach using gene, miRNA and Multiplex ELISA assay arrays coupled to integrative software to profile the mechanisms of action of PJ when deterring cancer progression of hormone insensitive prostate cancer cells.

 

Honors and Activities

Fulbright Fellowship; NRSA from NCI 1999-2001; Department of Defense Breast Cancer Review Panel, Immunology Study Section #2, 1998-2002; AHA panel on cardiovascular biology, 2004-2007; Nominee, Academic Achievement Junior Award, Women in Cell Biology, ASCB, 1998; Invited Speaker, Keystone Meeting on Chemokines and their Receptors, 1999; Organizer, pre-meeting sub-group symposium on "The Cell Biology of Chemokines in Host Defense, Wound Healing and Disease" for the annual ASCB meeting, 2000; Participant as a chemokine expert in a workshop sponsored by the Radiation Research Program, Division of Cancer Treatment and Diagnosis, NCI. September,2000 (see publication generated from this workshop); Member, Standing Committee on Women in Cell Biology of the American Soc. for Cell Biology, 2001-present; Speaker, Gordon Conference in Wound Repair and Regeneration, 2001, 2003, 2005, 2007; Speaker, ASCB 42nd Annual meeting in the Angiogenesis Minisymposium, 2001; Abstract selected for the ASCB Press Book, 2001; Chair, Bioengineering Session at the Wound Healing Society annual meeting, May 2002; Main speaker at the Gordon Conference in Vascular Biology, Ventura, CA, February 2003; Abstract selected for the ASCB Press Book, 2004; Chair of the Academic Senate for the UCR Division of the UC, 2004-06; Nominated for the ICOC, CA prop 71 Initiative, 2005; Abstract selected for the ASCB Press Book, 2006; Program co-Chair for the 2008 WHS Annual Meeting, 2008; Member of the Scientific Board for the TERMIS meeting in San Francisco 2008; Member of the UC committee to hire the new chancellor at UCR, 2007/8; UCR's Distinguished Service Award, 2008; UCR's Innovative Teaching Award, 2008; Guest Professor, Northwest University in Xian, China, 2008-present;Affiliated Professor of the Faculty of Medicine, University of Porto, Portugal, 2009-present; Assoc. Editor of BMC Cell Biology, 2009-present; Assoc. Editor of Creative Education (International Journal), 2009-present; Member Board of Directors of the UC School of Global Health, 2010-present.

New Approaches to Personalized Medicine: Inflammation, Healing, and Regeneration as Prototypes  

Click here for the program of the meeting.

Ranking of UCR and Dr. Martins-Green in the field of Chemokines and Wound Healing

Click here for the ranking of UCR in the field of Chemokins and Wound Healing

Click here for the ranking of Dr. Martins-Green in the field of Chemokines and Wound Healing

Publications

1.  Martins-Green, M. (1988). Origin of the dorsal surface of the neural tube by progressive delamination of epidermal ectoderm and neuroepithelium: Implications for neurulation and neural tube defects. Development 103: 687-706.  In this seminal paper as a graduate student, I proposed a novel way by which the neural tube develops and closes and the potential consequences for Spina bifida. My model was highlighted in a 1990 comprehensive review of mechanisms of neurulation as one of two important new ideas breaking ground on this subject and has been included in Developmental Biology textbooks.

2.  Martins-Green, M., M.J. Bissell (1990). Localization of 9E3/CEF4 in avian tissues:  Expression is absent in RSV-induced tumors but is stimulated by injury. J. Cell Biol.110: 581-595. (photo on journal cover).  In this paper we discovered that tumors that develop due to viral infection do not necessarily retain components of the virus that can be detected in diagnostic assays.  This was at the time a very unconventional proposition. Furthermore, we showed for the first time that chemokines are involved in response to injury caused by the tumor and in normal response to injury, in particular in the development of microvessels.

3.  Martins-Green, M., N. Boudreau, M.J. Bissell (1994). Inflammation is responsible for the development of wound tumors in RSV-infected newly-hatched chicks. Cancer Res. 54:4334-4341.  In this publication we showed that Rous-Sarcoma-Virus (RSV)-induced tumors were dependent on inflammation and proposed that during inflammation macrophages play a key role for viral-induced tumor development. We also proposed that this type of inflammation is instrumental in HIV infection and Aids because both injury and macrophages are critical for development of this disease.

4.  Feugate, J.E., QJ Li, S. Lu, M. Martins-Green (2001). The CXC chemokine cCAF stimulates differentiation of fibroblasts into myofibroblasts and accelerates wound closure in vivo. Journal of Cell Biology 156:161-172.  This study showed for the first time that chemokines stimulate another process of wound healing (contraction of the wound) in addition to angiogenesis, in this manner making solid the contributions of these small cytokines to wound healing, something that was not known previously. We obtained a patent for these findings.

5.  Li, Q-J., SH Yang, Y. Maeda, FM Sladek, AD Sharrocks, M. Martins-Green (2003). Map kinase phosphorylation-dependent activation of Elk-1 leads to activation of the coactivator p300. EMBO Journal 22(2): 1-11.  The work presented here made new and significant experimental and conceptual contributions to the field of transcription. We identified novel interactions between transcription factor and co-activator that could play a critical role in chromatin remodeling and gene activation. This mechanism may be important in regulation of expression of immediate early response genes, in particular those involved in stress responses.

6.  Li, QJ, M. Yao, W. Wong, V. Parpura, M. Martins-Green. (2004). The N- and Cterminal peptides of hIL8/CSCL8 are ligands for hCXCR1 and hCXCR2. FASEB, 10:10961/fj.02-1175fje. Short summary published in FASEBJ 18:776-778, 2004. Using the chemokine IL-8/CXCL8, we discovered that multifunctionality of chemokines is related to the function of peptides that represent not only the N-terminus but also the C-terminus of these highly conserved molecules and that their functions lead to different outcomes. Previously, only the N-terminus of chemokines was thought to have functionality.

7.  Martins-Green, M. Q-J Li and Min Yao (2005). Engineering human skin in culture using primary adult cells. FASEB J. 19:222-4, FASEB Dec 9, 2004 [Epub].  This paper introduces a new generation of organ cultures that mimics human skin. This system can help answer fundamental biological and medical questions and can potentially be developed to help with impaired healing. This prototype points the way to development of more complex tissue and organ cultures prepared with adult human primary cells for studies of disease, testing of drugs, and potential application as replacement organs.

8.  Petreaca, M., M. Yao, C. Ware, and M. Martins-Green (2008). VEGF promotes macrophage apoptosis through stimulation of tumor necrosis factor superfamily member 14 (Tnfsf14/LIGHT). Wound Repair and Regeneration, 16:602-614. [Winner of a Young Investigator Award in 2006].  In this work we challenged the established paradigm that VEGF is a survival factor by demonstrating that it stimulates macrophage death during inflammation in vivo and that this process of resolution of inflammation occurs through LIGHT.

9.  Yuan, Hongwei, John Y-J Shyy, Manuela Martins-Green (2009). Second-Hand Smoke Stimulates Lipid Accumulation in the Liver by Modulating AMPK and SREBP-1. Journal of Hepatology 51: 535-547.  This paper showed for the first time that second-hand cigarette smoke causes nonalcoholic fatty liver disease (NAFLD) which involves accumulation of fat in liver cells. We further unraveled the mechanism by which this process occurs. Cigarette smoke inhibits AMPK function that, in turn, releases the brakes on the transcription factor SREBP which then turns on lipid synthesis. This disease leads to non-alcoholic steatohematosis (inflammation of the liver), followed by cirrhosis and eventually liver failure. The journal solicited an extensive editorial (reference follows this paragraph) that was published along with the paper and emphasized the fundamental importance of the work presented in this paper. More than 40 news articles were published about this work worldwide.  Ariane Mallat*, Sophie Lotersztajn (2009). Cigarette smoke exposure: A novel cofactor of NAFLD progression? Editorial, Journal of Hepatology 51:430-432.

10.  Hongwei Yuan, Chongze Ma, Lisa Moinet, Noboru Sato and Manuela Martins-Green (2010). Thymosin â4 in combination with anti-inflammatory agents reverses “second-hand” cigarette smoke-induced impairment of cornea wound healing. Investigative Ophthalmology & Visual Science 51:1-12.  This work shows that the effects of second-hand cigarette smoke toxicants on inhibition of cornea healing can be reversed by treatment with both anti-inflammatory agents and Thymosin β4. These results can be directly applied to the clinic because a variety of anti-inflammatory agents and Thymosin β4 are approved by the FDA.

 Complete Curriculum Vitae


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