McAllister Heart Institute

Medicine Lodge, United States

McAllister Heart Institute

Medicine Lodge, United States
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Peirce S.M.,University of Virginia | Gabhann F.M.,Johns Hopkins University | Bautch V.L.,University of North Carolina at Chapel Hill | Bautch V.L.,McAllister Heart Institute
Current Opinion in Hematology | Year: 2012

Purpose of Review: We summarize recent experimental and computational studies that investigate molecular and cellular mechanisms of sprouting angiogenesis. We discuss how experimental tools have unveiled new opportunities for computational modeling by providing detailed phenomenological descriptions and conceptual models of cell-level behaviors underpinned by high-quality molecular data. Using recent examples, we show how new understanding results from bridging computational and experimental approaches. Recent Findings: Experimental data extends beyond the tip cell vs. stalk cell paradigm, and involves numerous molecular inputs such as vascular endothelial growth factor and Notch. This data is being used to generate and validate computational models, which can then be used to predict the results of hypothetical experiments that are difficult to perform in the laboratory, and to generate new hypotheses that account for system-wide interactions. As a result of this integration, descriptions of critical gradients of growth factor-receptor complexes have been generated, and new modulators of cell behavior have been described. Summary: We suggest that the recent emphasis on the different stages of sprouting angiogenesis, and integration of experimental and computational approaches, should provide a way to manage the complexity of this process and help identify new regulatory paradigms and therapeutic targets. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

News Article | November 17, 2016

Inspired by a genetic discovery by her Ph.D. mentor, UNC heart researcher Li Qian followed the 'Tinman' down the yellow brick road to an award-winning career in science Scientist Li Qian, PhD, has forged an award-winning career at the UNC School of Medicine. In just a few short years since joining the faculty, she's been recognized for her cardiac research by The American Heart Association. She was the first-ever recipient of the Boyalife, Science and Science Translational Medicine Award in Stem Cell and Regenerative Medicine. And now she has earned a UNC School of Medicine Jefferson-Pilot Fellowship in Academic Medicine, which includes $20,000 to be used toward scholarly endeavors. We caught up with Qian, assistant professor of pathology and laboratory medicine at the UNC School of Medicine and member of the McAllister Heart Institute, to discuss her research in cardiac reprogramming, her goal to inspire young women to pursue careers in science, and how and why she chose the UNC School of Medicine. As a young girl growing up in China, did you ever imagine you'd spend your career in science, studying the heart, at a university in the United States? What were some of the obstacles you've had to overcome to follow your dreams? When I was little, I was always encouraged to do what I wanted and follow my dreams, especially pursuing my interest in science. My parents both work for a university. My dad is a professor of engineering and my mom is an accountant. I was quite fortunate that we lived in a positive and open environment - one that fostered the growth that's critical for one's future success. I was drawn to science by curiosity as a kid. I clearly remember the first time I ever saw a cell under a microscope. It was the onion cell experiment. Ever since then, I have always been fascinated by the question of how a single cell becomes an organ and, ultimately, becomes a whole life form. At the time I graduated from college in China, one of the best places to do basic research was the States because of its reputation in basic science, the opportunity to work with world-renowned scientists and the strong infrastructure and cutting-edge technology. I also like the diversity, openness and welcoming atmosphere to people from different backgrounds. However, as an incoming international student, getting started in a completely different environment was extremely challenging. Imagine the language barriers I had when I first came to this country. I could barely understand a sentence if the conversation was not face-to-face. My PhD mentor, Rolf Bodmer, witnessed and complimented me when he realized that I followed the American dream by growing from a shy international student into a dynamic young leader in science. You always knew that you wanted to pursue some field of science. How did you become interested in the heart? It was the story of the "Tinman." In the 1980s, I read in the news that a neurobiologist at the University of Michigan used fruit flies to identify master genes that regulate neuronal cell fate. He was screening for important transcription factors critical in the development of the peripheral nervous system, but serendipitously identified a homeobox gene that, when mutated, resulted in the absence of heart formation in the fruit fly. He was fascinated by this discovery and named the gene the Tinman, which is a reference to "The Wizard of Oz." This work was published in 1989, and after that follow-up studies identified the vertebrate counterpart of the Tinman gene, NKX2.5. By studying a family in Pennsylvania with a high incidence of congenital heart disease, scientists from Harvard University found that the disease was caused by a mutation in NKX2.5. The scientist who identified Tinman was Dr. Bodmer, my PhD mentor. His work opened up the field and I was lucky to have a chance to work with him in his lab. Your research is now focused on cardiac reprograming - converting cardiac scar tissue cells into functional cardiomyocytes. What are your immediate and long-term goals for this research? Basic research is so important. We never know how basic research will be used in identifying factors that cause diseases. When Rolf discovered the Tinman gene, he did not know that there would be a family whose cardiac disease could be traced back to that gene. For me, I want to see my research and my approach used on a patient. That's the immediate goal, within five to 10 years. I know there's so much research that needs to be done to really help a patient one day. It will take some time, but we are collaborating with many labs in the field and we share with them our unpublished data to accelerate the field. And it's only if we all work together to accelerate our research that we can realize our goal of helping patients with our approach as soon as possible. But, in terms of career goals, it never ends. In terms of heart disease, there are always new diseases that are being discovered. One therapy might be a good treatment, but then a better treatment might come along. We always try to address the most urgent, most challenging question in the field. But it's always changing. I think my lab will continue to take on the major challenges in the field. Even with reprogramming, our lab will work to develop therapies and targeted medicine beyond the type of cardiac disease we are working on now. Research-wise, there's just no end. There are so many things I can do. You've mentioned that mentorship - both as a mentor and a mentee - played a big part in your early career and why you made the decision to come to UNC. Why is that so important to you? It's incredibly important to me to help mold young scientists, especially young women scientists in this field. My lab has a lot of young women trainees. It's very rewarding for me to mentor and promote the next generation of scientists. I am grateful that my former mentors trained me in a very positive, encouraging, and supportive manner. It helps to build a positive research environment that fosters the love of science and the spirit of teamwork. UNC has a lot of brilliant women studying, doing research, and practicing medicine, and that really influenced my decision to join the faculty here. UNC has done such a wonderful job in promoting women scientists. That's a very effective way to attract young female scientists to come here to start their careers. At multiple levels, they are viewed as role models for young scientists, especially young women scientists. Your husband is also a basic scientist at UNC who studies the heart. What are your family dinner conversations like? Do you encourage your daughters to pursue careers in science or medicine? Although we are both scientists, we talk about a lot of different things at our dinner table, from things that happened in my daughters' school, their love for ice skating, and, of course, science. Because of these conversations, my older daughter, who is now 10, has asked me about cell reprograming and how it works. I fully respect their choices they make for their education and their careers when they grow up. I encourage them to find their passions and follow their dreams, but I will also certainly create an environment for them so that they will be exposed to science and technology. I go to my daughters' schools to give lectures a few times a year. Science and biology are a big part of it, but it's not just to share the science. It's to tell the students: anything is possible; be wild and be crazy with your goals; be brave, and go on to realize your goals and your dreams.

Xiao L.,University of North Carolina at Chapel Hill | Harrell J.C.,Lineberger Comprehensive Cancer Center | Perou C.M.,Lineberger Comprehensive Cancer Center | Perou C.M.,University of North Carolina at Chapel Hill | And 3 more authors.
Angiogenesis | Year: 2014

Long-term, in vitro propagation of tumor-specific endothelial cells (TEC) allows for functional studies and genome-wide expression profiling of clonally derived, well-characterized subpopulations. Using a genetically engineered mouse model of mammary adenocarcinoma, we have optimized an isolation procedure and defined growth conditions for long-term propagation of mammary TEC. The isolated TEC maintain their endothelial specification and phenotype in culture. Furthermore, gene expression profiling of multiple TEC subpopulations revealed striking, persistent overexpression of several candidate genes including Irx2 and Zfp503 (transcription factors), Alcam and Cd133 (cell surface markers), Ccl4 and neurotensin (Nts) (angiocrine factors), and Gpr182 and Cnr2 (G protein-coupled receptors). Taken together, we have developed an effective method for isolating and culture-expanding mammary TEC, and uncovered several new TEC-selective genes whose overexpression persists even after long-term in vitro culture. These results suggest that the tumor microenvironment may induce changes in vascular endothelium in vivo that are stably transmittable in vitro. © 2013 Springer Science+Business Media Dordrecht.

Dunleavey J.M.,University of North Carolina at Chapel Hill | Dudley A.C.,University of North Carolina at Chapel Hill | Dudley A.C.,Lineberger Comprehensive Cancer Center | Dudley A.C.,McAllister Heart Institute
Current Angiogenesis | Year: 2012

As in normal tissues, solid tumors depend on vascular networks to supply blood, oxygen, and nutrients. Tumor blood vessels are formed by common processes of neovascularization for example endothelial sprouting. However, some tumors have alternative and unexpected mechanisms of neovascularization at their disposal. In a process termed vascularmimicry, tumors create their own, tumor cell-lined channels for fluid transport independent of typical modes of angiogenesis. These tumor cell-lined conduits may express endothelial-selective markers and anti-coagulant factors which allow for anastamosis with host endothelium. In this review, we explore the current status of vascular mimicry research, highlighting recent evidence which strengthens the hypothesis for this unusual ability of tumor cells. Furthermore, we address the theoretical possibility that vascular mimicry provides a mechanism whereby tumors could escape antiangiogenic therapies. © 2012 Bentham Science Publishers.

Chen Z.,University of North Carolina at Chapel Hill | Rubin J.,McAllister Heart Institute | Rubin J.,University of North Carolina at Chapel Hill | Tzima E.,University of North Carolina at Chapel Hill | Tzima E.,McAllister Heart Institute
Circulation Research | Year: 2010

Rationale: Hemodynamic forces caused by the altered blood flow in response to an occlusion lead to the induction of collateral remodeling and arteriogenesis. Previous work showed that platelet endothelial cell adhesion molecule (PECAM)-1 is a component of a mechanosensory complex that mediates endothelial cell responses to shear stress. Objective: We hypothesized that PECAM-1 plays an important role in arteriogenesis and collateral remodeling. Methods and Results: PECAM-1 knockout (KO) and wild-type littermates underwent femoral artery ligation. Surprisingly, tissue perfusion and collateral-dependent blood flow were significantly increased in the KO mice immediately after surgery. Histology confirmed larger caliber of preexisting collaterals in the KO mice. Additionally, KO mice showed blunted recovery of perfusion from hindlimb ischemia and reduced collateral remodeling, because of deficits in shear stress-induced signaling, including activation of the nuclear factor κB pathway and inflammatory cell accumulation. Partial recovery was associated with normal responses to circumferential wall tension in the absence of PECAM-1, as evidenced by the upregulation of ephrin B2 and monocyte chemoattractant protein-1, which are 2 stretch-induced regulators of arteriogenesis, both in vitro and in vivo. Conclusions: Our findings suggest a novel role for PECAM-1 in arteriogenesis and collateral remodeling. Furthermore, we identify PECAM-1 as the first molecule that determines preexisting collateral diameter. © 2010 American Heart Association, Inc.

Wadosky K.M.,McAllister Heart Institute | Willis M.S.,McAllister Heart Institute | Willis M.S.,University of North Carolina at Chapel Hill
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2012

Many studies have implicated the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptor transcription factors in regulating cardiac substrate metabolism and ATP generation. Recently, evidence from a variety of cell culture and organ systems has implicated ubiquitin and small ubiquitin-like modifier (SUMO) conjugation as post-translational modifications that regulate the activity of PPAR transcription factors and their coreceptors/coactivators. Here we introduce the ubiquitin and SUMO conjugation systems and extensively review how they have been shown to regulate all three PPAR isoforms (PPARa, PPAR(3/8, and PPAR7) in addition to the retinoid X receptor and PPAR7 coactivator-1a subunits of the larger PPAR transcription factor complex. We then present how the specific ubiquitin (E3) ligases have been implicated and review emerging evidence that post-translational modifications of PPARs with ubiquitin and/or SUMO may play a role in cardiac disease. Because PPAR activity is perturbed in a variety of forms of heart disease and specific proteins regulate this process (E3 ligases), this may be a fruitful area of investigation with respect to finding new therapeutic targets. © 2012 by the American Physiological Society.

Dudley A.C.,University of North Carolina at Chapel Hill | Dudley A.C.,Lineberger Comprehensive Cancer Center | Dudley A.C.,McAllister Heart Institute
Cold Spring Harbor Perspectives in Medicine | Year: 2012

The vascular endothelium is a dynamic cellular "organ" that controls passage of nutrients into tissues, maintains the flow of blood, and regulates the trafficking of leukocytes. In tumors, factors such as hypoxia and chronic growth factor stimulation result in endothelial dysfunction. For example, tumor blood vessels have irregular diameters; they are fragile, leaky, and blood flow is abnormal. There is now good evidence that these abnormalities in the tumor endothelium contribute to tumor growth and metastasis. Thus, determining the biological basis underlying these abnormalities is critical for understanding the pathophysiology of tumor progression and facilitating the design and delivery of effective antiangiogenic therapies. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.

Willis M.S.,McAllister Heart Institute | Willis M.S.,Laboratory Medicine | Townley-Tilson W.H.D.,Cell and Developmental Biology | Kang E.Y.,McAllister Heart Institute | And 4 more authors.
Circulation Research | Year: 2010

The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia/reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible because of their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative "specific" mechanisms. The cytosolic receptors p62, NBR, and histone deacetylase 6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of "selective autophagy." Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease. © 2010 American Heart Association, Inc.

Wang J.-G.,McAllister Heart Institute | Williams J.C.,McAllister Heart Institute | Davis B.K.,Lineberger Comprehensive Cancer Center | Jacobson K.,University of North Carolina at Chapel Hill | And 3 more authors.
Blood | Year: 2011

Microparticles (MPs) are shed from activated and dying cells. They can transmit signals from cell to cell, locally or at a distance through the circulation. Monocytic MPs are elevated in different diseases, including bacterial infections. Here, we investigated how monocytic MPs activate endothelial cells. We found that MPs from lipopolysaccharide (LPS)-treated THP-1 monocytic cells bind to and are internalized by human endothelial cells. MPs from LPS-treated THP-1 cells, but not untreated cells, induced phosphorylation of ERK1/2, activation of the nuclear factor-κB pathway and expression of cell adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. Similar results were observed using MPs from LPS-treated peripheral blood mononuclear cells. We next investigated the mechanism by which monocytic MPs activated endothelial cells and found that they contain IL-1β and components of the inflammasome, including apoptosis-associated speck-like protein containing a CARD, caspase-1, and NLRP3. Importantly, knockdown of NLRP3 in THP-1 cells reduced the activity of the MPs and blockade of the IL-1 receptor on endothelial cells decreased MP-dependent induction of cell adhesion molecules. Therefore, monocytic MPs contain IL-1β and may amplify inflammation by enhancing the activation of the endothelium. © 2011 by The American Society of Hematology.

Kushner E.J.,University of North Carolina at Chapel Hill | Bautch V.L.,University of North Carolina at Chapel Hill | Bautch V.L.,McAllister Heart Institute | Bautch V.L.,Lineberger Comprehensive Cancer Center
Current Opinion in Hematology | Year: 2013

Purpose of Review: This review will examine developmental angiogenesis and tumor-related changes to endothelial cells. Recent Findings: Processes that govern developmental angiogenesis become dysfunctional in the tumor environment, leading to abnormal tumor endothelial cells and blood vessels. Recent findings suggest that tumor endothelial cells are permanently modified compared with normal counterparts. Summary: Coordination of numerous intracellular and extracellular programs promotes the formation of new blood vessels that are necessary for both development and certain diseases. Developmental angiogenesis uses canonical signaling modalities to effectively assemble endothelial cells into predictable vessel structures, and disruption of critical signaling factors has dramatic effects on blood vessel development. Solid tumors co-opt developmental cues to promote formation of tumor vessels that sustain their growth, but these angiogenic signals are not well regulated and produce endothelial cell dysfunction. Aberrant growth factor signaling contributes to phenotypic changes and acquired irreversible intracellular signaling, cytoskeletal and genetic modifications in endothelial cells of tumor vessels. Permanently altered tumor endothelial cells may represent a significant population. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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