Cell Biology and Neuroscience

Manuela Martins-Green

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

Manuela Martins-Green

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


Research Program

My research program focuses on understanding the cell and molecular mechanisms involved in normal and abnormal healing, the effects of natural products on prostate cancer metastasis and engineering of tissue with primary human cells to answer mechanistic questions.

Wound Healing
1.  Normal Processes.
I pioneered investigation of the role of chemokines in wound healing. 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 cancer. 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 #4 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 were 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 developed a transgenic humanized mouse model in which human CXCR1 is expressed in all tissues but can be activated in a given 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.

wound healing

2.  Impaired healing.
(a) Effects of cigarette smoke toxicants on healing. Our goal is to identify key processes affected by cigarette smoke and which chemicals in the smoke cause those effects. We investigate the effects of second-hand smoke (SHS) on: (a) skin wound healing; (b) cornea epithelial wound healing; (c) the development of atherosclerotic plaques (a form of impaired healing of blood vessels) and (d) liver function in response to chemical injury. These latter studies also led us to discover that second hand cigarette smoke stimulates high levels of circulating triglycerides which are a major factor in development of non-alcoholic fatty liver disease (NAFLD), a condition that leads to liver cirrhosis and ultimately to liver failure. We have identified a molecular pathway involving AMPK by which SHS stimulates NAFLD. To further understand the effects of cigarette smoke on liver biology and pathology, we are planning on developing a human liver lobule. With this engineered tissue we will be able to understand the effects of the smoke toxins on the liver in order to determine how the liver detoxifies and how it metabolizes the toxins so that ways can be developed to prevent liver disfunction. We have recently engaged in studies of Third Hand Smoke (THS) effects on healing and on other aspects of the body physiology. THS is composed of the chemicals that remain in the environment after SHS dissipates. It can be more dangerous than SHS because if combines with various environmental chemicals to form carcinogens that can be picked up by children and elderly people living in houses of smokers. We have found that THS affects healing (wounds close poorly), liver function (causes NAFLD), lung function (accumulation of molecules that contribute to fibrosis) and even behavior (mice exposed to THS from the time they are weaned until they are teenagers show hyperactive behavior).
(b) Using genetic manipulations, we have also developed a mouse model for chronic wound development. We are deciphering the molecular mechanisms by which these wounds develop with the idea of identifying specific molecular pathways that can be targeted both for diagnosis and treatment.
(c) We are using Insulin to treat burn wounds to improve healing and, in particular, 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.

3.  Cancer Metastasis. 
Effects of Pomegranate Juice in inhibiting metastasis of hormonal cancers.
We are currently studying the effects of Pomegranate Juice (PJ) on 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. We have identified three components of the juice that, together, mimic the effects of the whole juice. This is an important finding because PJ is a very complex mixture of components and is found in many different formulations; it is important to identify specific components that can replace the effects of the juice on growth and metastasis. An abstract on this subject was chosen by the Faculty of One Thousand to be featured on their website in 2009 and. in 2010 another abstract was selected for the Press Book of the American Society for Cell Biology Annual Meeting. Preliminary results show that PJ and its components show the same effect on breast cancer cells.

4.   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 develop 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. Finally, in collaboration with a colleague at West Virginia University, we are engineering blood vessels into the organ culture I have developed previously, with the idea to apply controlled flow to study endothelial cell function under conditions of stress and exposure to toxins.

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.

Selected References

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.

11.  Wang, Lei, Andre Alcon, Hongwei Yuan, Jing Li and Manuela Martins-Green (2011). Cellular and Molecular Mechanisms of Pomegranate Juice-Induced Anti-Metastatic Effect on Prostate Cancer Cells. Integrative Biology 3: 742-754 DOI: 10.1039/c0ib00122h.

12.  Wang, Lei, Jeffrey Ho, Carlotta Glackin and Manuela Martins-Green (2012). Specific Pomegranate Juice Components as Potential Inhibitors of Prostate Cancer Metastasis. Translational Oncology 5: 1-12.

13.  Ana Rocha, Lei Wang, Manuela Penichet and Manuela Martins-Green (2012). Pomegranate Juice and Specific Components Inhibit Cell and Molecular Processes Critical for Metastasis of Breast Cancer Cells. Breast cancer Research and Treatment. In Press.   These three papers focus on the effects of Pomegranate Juice and three of its components on inhibiting cell and molecular mechanisms that are critical for metastasis of cancer cells. Because we have tested both prostate and breast cancer cells and obtained similar results we can safely say that the three components of pomegranate juice can inhibit metastasis of cancer cells in general.

14.  Huang, Zhouchun, Li, Xiang, Manuela Martins-Green and Liu, Yuxin (2012). Microfabrication of Cylindrical Microfluidic Channel Networks for Microvascular Research. Lab on a Chip. Biomed Microdevices DOI: 10.1007/s10544-012-9667-2.   In this paper we used the system I developed (above) to build microvessels in a controlled manner so that we can now study mechanism of various functions of endothelial cells including inflammation and drug-induced permeability of the microvessels, atherosclerotic plaque initiation, etc..

Administrative Experience

      For two years (2004-06) I served as Chair of the Riverside Division of the Academic Senate of the University of California. This is an elected position for a period of two years. When I assumed this position the Academic Senate Office and the Senate in general were disfunctional. I immediately garnered resources from the Chancellor and the executive Vice-Chancellor to turn the office into a functional unit and to be able to engage the faculty into participating and taking responsibility for their portion of the shared governance that is the hallmark of the UC system. I summarize here the major accomplishments during my tenure as Chair. (1) Brought greater visibility and stature of the Senate in the eyes of the Administration and also in the eyes of the Statewide Senate. (2) Increased the number of FTE in the Senate office to a total of 5.5 FTE when I left, from 2 when I came in. To accommodate the new FTE, we renovated the office and acquired additional space. By the time I left, the staff was fully equipped and qualified to carry out all of the functions of the Senate committees. (3) As a result of numerous complaints, I formed an Ad-hoc committee on Faculty Advancement to look into issues of merits and promotion and faculty advancement at UCR compared to the other campuses and the possibility of bringing CAP to the Senate from the office of the Vice Provost for Academic Personnel (this was accomplished in the Fall of 2006). (4) Initiated reviews of the General Education Curriculum: developed policy for systematic review of Undergraduate Programs and reviewed the structure of the Life Sciences Undergraduate Programs. I also initiated the process of bringing the conversion factor to 1.0, which is critical for bringing more resources to the campus and developed and implemented a new teaching evaluation form. (5) Continued to develop means to re-engage the faculty with the Senate. (6) Finally, I delineated a number of issues that needed to be brought to fruition by the next chair: **work on curricular reform, **engage more faculty in Senate service, **enhance fairness in merits and promotions; **re-evaluate the way that faculty is given credit for teaching **bring back an appropriate salary scale that is compatible with market compensation. For my many accomplishments in this position, I was awarded the 2008 Distinguished Service Award for the UCR Campus. Now, 6-years later, the Riverside Division of the Academic Senate is still a vibrant organization.


      Climbing the hill of academic success is significantly steeper for women in general and for women and men of any ethnic group. I, myself, experienced and many of my mentees have experienced very difficult episodes along the way. One of the things that I have learned is that a great many of the discriminatory acts that women experience are not purposeful but are products of unconscious patterns and expectations followed by both male and female faculty members, administrators and staff. I presume that also is probably the case for much of the modern discrimination against men of color. As a consequence, mentoring of young women and minorities has a very important educational component concerning the pitfalls to look out for, the ability to identify critical issues to which attention should be given, and ways to address the problems without compromising one's career. To that end, I have been active since early in my career in matters of equality and diversity on my campus of the University of California (Riverside), across the larger University of California, and in my principal scientific organizations, the American Society for Cell Biology (ASCB) and the Wound Healing Society (WHS).

Academic Mentoring
      Early in my career at UCR, I was a member of the Diversity Initiative Task Group on Faculty Hiring (1995-6) and I continued in a variety of informal ways, including searching out two informal mentors for myself, one within my own department and another from outside my department. The former was a great help to me in good times and in bad but the latter turned out to be a very unfortunate choice that actually delayed my career advancement. One positive aspect of that experience, however, was that I made up my mind that when I reached the appropriate level to be a mentor, I would take every opportunity available to me to be active and dedicated to making the pathway easier for those women who come after me.

      My formal opportunities began when I was selected as the UCR representative to the UC Presidential Summit on Gender Equity in 2002. Almost simultaneously I was elected to the UCR Committee on Committees, an important committee that appoints the members of all other committees of the pertinent campus Divisional Academic Senate. There I had the opportunity to recommend and support the names of women and minorities whom I thought would be excellent representatives on various committees. I became Chair of that committee in 2003/4 and was elected Chair of the Riverside Division of the Academic Senate for 2004-6, a position that gave me the ear of the upper administration on the campus and a seat on the Academic Council of the entire University. Being Chair of the Senate also brought me face-to-face with many problems of individual faculty and faculty groups whom I mentored informally for short or long times as the issue(s) required. I also began at that time to mentor junior faculty women, many of whom sought me out for advice. Since that time, I have mentored (and in some cases continue to mentor) junior faculty women, most of whom are, like me, foreign born. So far, I have formally mentored 4 female junior faculty from the College of Engineering. One is now a professor at UCR who has won numerous awards, another successfully obtained tenure but then decided to leave and is doing very well at a major university, a third is progressing very well, having won a CAREER Award and a BRIGE award from the NSF and the most recent one is adapting well to the UC system. A 5th, an assistant professor of engineering at a university in a different state, has scientific connections to my work and she requested that I become her mentor. As a result of these interactions, we competed for an NSF ADVANCE Award that was won by her institution and we received funds to support the long-distance mentorship. We are collaborating on a tissue engineering project that is based on an organ culture of human skin that I published in 2004. She is currently engineering blood vessels into my system to enable study of fundamental functions of endothelial cells under conditions of controlled flow.

      During and following my term as Senate Chair, I have served in several formal capacities relevant to diversity and mentoring of students as well as junior faculty:

    2005:    While a member of the Academic Council, I was asked by the President of the Council to make a presentation, in conjunction with the Executive Vice Chancellor from UC Santa Barbara, on the status of Affirmative Action to a joint meeting of the Academic Council and the Council of EVCs of all of the campuses. Our propositions for change were very well received

    2007-08:    Beckman Mentor, College of Sciences, for mentoring undergraduates in research

    2007-10:    Member, UCR Senate Faculty Welfare Committee

    2009-10:    Member, UCR campus Strategic Planning Committee on Climate and Communication.

    2010-11:    Chair, UCR Senate Committee on Diversity and Equal Opportunity (CODEO). While serving as chair of this committee we requested that the Vice Provost of Academic Personnel Office provide us with the statistics of diversity of the UCR faculty and administration. We studied the data and at the end of the year made a presentation to the Chancellor. He was very receptive to our report and I have been happy to see that, we now have a woman for Dean of the College of Natural and Agricultural Sciences (the first in the history of the College) and she has appointed two women as department chairs and has chosen a woman as one of her Associate Deans. Not bad progress in one year.

    2010-11:    Member, UC-wide Committee on Affirmative Action and Diversity (UCAAD)

    2010-13:    Member, Chancellor's Council on Campus Climate, Communication and Inclusion

    2010-14:    Member, UC President's Faculty Diversity Working Group of the Advisory Council on Climate, Culture, Communication and Inclusion (CCC&I)

    2011-12:    Vice-Chair, UCAAD (University of California Committee on Affirmative Action and Diversity)

    2012-13:    Chair, UCAAD (University of California Committee on Affirmative Action and Diversity)

Professional Mentoring
      I served 2001-2007 on the Women in Cell Biology Standing Committee of the American Society for Cell Biology (ASCB), a committee focused primarily on mentoring of young faculty. I also served for the same period on the Standing Committee on Education of the ASCB. More recently, I have been extremely active in many aspects of the Wound Healing Society, primarily dedicated to program and meeting development, but all the while with an eye to rewarding excellence and promoting gender equity through organization of the Meet the Mentor Session at the Annual Meeting of the Society. This has been particularly true in my service 2009-2011 as Chair of the Awards Committee of the WHS where I have worked for excellence that is inclusive of diversity.

 Complete Curriculum Vitae

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Cell Biology and Neuroscience
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