Inflammatory disease research - Our laboratory's main research focus is to understand the molecular basis of immunoregulatory and inflammatory diseases such as autoimmune lupus. In these disorders, there is a defective regulation of both peripheral lymphoid organs (such as spleen) and central lymphoid organs (such as bone marrow and thymus). Abnormal differentiation of stem cells in the bone marrow and the thymus results in the generation of autoreactive cells. These cells are capable of secreting damaging inflammatory cytokines, and attacking and destroying self-tissues. Our laboratory has been studying how various transcription factors and microRNAs control the expression of inflammatory cytokines. It is now known, that these small microRNAs regulate the expression of genes including inflammatory genes. Dysregulation of microRNAs is now evident in many diseases. Our laboratory has identified a signature expression of microRNAs in splenic lymphocytes from lupus and in estrogen-induced inflammation. We are attempting to correct these disorders by using strategies to counter these microRNAs. It is logical to assume that stem cells in the bone marrow and thymus of autoimmune mice will also demonstrate unique alterations in expression patterns of microRNAs. The identification of signature microRNAs will allow us to design strategies to re-calibrate the expression of dysregulated micoRNAs and hopefully prevent the generation of autoreactive cells. Learn more
Orthopedic tissue engineering research - Elucidating the subtle pathways driving stem cell differentiation is critical to understand the molecular mechanisms of repair, as well as to develop novel therapeutics in regenerative medicine. Our laboratory is primarily interested in the anti-inflammatory and tissue-regenerative properties inherent to adult stem cells resident in tendon, bone marrow, and adipose tissue. Our current projects investigate the influence of micro-environmental manipulation on cellular behavior through the use of topographically variable matrices, dynamic mechanical bioreactors and variations in growth factor concentrations. Learn more
Cancer research - We use a mouse model system built on nonrandom chromosomal translocations associated with leukemogenesis to understand how fusion genes influence the development of bone marrow stem cells during malignancy. We are focused on the bone marrow microenvironment and how its role influences the malignant transformation of hematopoietic cells. To address these issues, we use genetically engineered mice that develop Myelodysplastic syndrome, acute leukemia, and myleofibrosis. Using these model systems we can investigate the role of hematopoietic progenitor cells including megakaryocytes, the cells that give rise to platelets. Through the use of genetically engineered mice, we can model important hematological diseases seen in people. By investigating the molecular pathogenesis of hematological malignancies in mice, he can understand more about normal hematopoiesis, as well as identify potential therapeutic targets for treatments to alleviate human suffering and death due to the burden of cancer. Learn more
Comparative Musculoskeletal Research - Our laboratory is focused on a comparative approach to the biology and healing of tendons and ligaments. We are interested in the role that adult stem cells may play in equine tendon regeneration and in particular the ability of the nucleated cell fraction from adipose tissue to function as trophic mediators of tissue healing. Through a more complete understanding of the soluble factors produced by these cells and their effects on endogenous progenitor and adult cells, we hope to develop improved biological approaches to enhancing tendon and ligament healing. In collaboration with faculty in the College of Engineering, we are also developing ligament engineering approaches for the treatment of anterior cruciate ligament injuries in people. We hope to use gradients of scaffold architecture and growth factor delivery to recapitulate the transitional architecture necessary to provide a biologically relevant bone/ligament/bone unit for ligament replacement. In addition, we are investigating methods to facilitate differentiation of adult stem cells down a tendon/ligament lineage for use in association with both of the above areas of research. Learn more
Heart research - Human stem cells are groups of cells isolated from either embryo (e.g., human embryonic stem cells, hESCs), different tissues of human organs (e.g, cardiac stem cells, CSCs) or through reprogramming the terminated somatic cells (e.g., induced pluripotent stem cells, iPSCs). These cells have demonstrated the capability of self-renewal and are able to differentiate into many cell types in the body. Therefore, stem cells provide great promise as a new approach for cell-based therapy to treat multiple diseases, including heart diseases. Recently our lab isolated a novel type of CSCs and we are interested in using these and also human iPSCs to study cardiac lineage differentiation, to define the functional and biological properties of differentiated cardiac cells, to generate engineered stem-cell tissues, and to understand the underlying mechanism of stem cell-based therapy for heart diseases in animal models. The overall goal is to establish new therapeutic approaches and eventually to transfer these techniques into human clinical trials for repairing ischemic cardiac diseases. Learn more
Vascular Biology - Research activities in our lab seek to gain a more comprehensive understanding of cellular signaling mechanisms that govern the development, repair, and pathophysiologic expansion of the peripheral vasculature. In particular, we are interested in how endothelial cells and their stem cell progenitors acquire and modulate their responsiveness to the angiogenic growth factor VEGF. Ongoing projects are investigating: 1) alternative RNA processing events leading to expression of sFlt1, a truncated, secreted VEGF receptor isoform that acts as an endogenous VEGF antagonist; 2) interactions between the intracellular signaling pathways activated by VEGF and insulin in endothelial cells; and 3) the dynamics of global gene expression patterns during development of the placenta from its proto-vascular precursor elements. We expect that insight gained from these studies will facilitate the identification of novel targets to control pathologic angiogenesis associated with neoplasia or retinopathies. Further, we anticipate that new strategies may emerge to promote neovascularization of either ischemic endogenous tissues or tissues derived from advancing applications of regenerative medicine. Learn more
Bone marrow research - Our laboratory is interested in the microenvironment in the bone marrow, which includes hematopoietic stem cells, mesenchymal stem cells, and certain lymphocytes (e.g. memory plasma cells) that have been recently suggested to function as adult stem cells. We use both in vitro culture systems and in vivo mouse models to explore therapeutic uses of these stem cells. For example, we could program hematopoietic stem cells to carry a therapeutic antibody against a life-threatening disease such as systemic lupus erythematosus. After systemic transplantation of the modified stem cells, which will reconstitute the immune system, the B cell-lineage progeny will continuously produce the therapeutic antibody against lupus to prevent disease relapse. This approach has great potential for translational medicine because it is broadly applicable to any diseases that can benefit from stem cell transplantation therapy. Learn more
Cancer research - Our laboratory, in collaboration with the Schmelz laboratory in HNFE, is actively investigating the microenvironment of visceral fat pads as a consequence of obesity and ovarian cancer peritoneal dissemination. One of our main objectives is to understand how the hematopoietic and mesenchymal stem cell populations are modulated in response to these two disease states. We are specifically interested in elucidating how cancer stem-like cells recruit hematopoietic/mesenchymal stem cells to different sites in order to aide in metastatic cell seeding and outgrowth. We employ a combination of multicellular spheroids comprised of adipose derived stem cells, endothelial progenitor cells, hematopoietic progenitors and ovarian cancer stem-like cells to examine differentiation of the stem cells under different microenvironmental conditions, including normoxia and hypoxia. Coupling in vivo tumor spheroid assessment under obese and lean states will allow us to fully assess the impact of stem cell expansion under obese conditions on tumor cell dissemination within the peritoneal cavity. Learn more
Stem cell-based approaches to cancer research - Cancer stem cells represent a new paradigm in tumor biology. While traditional cancer therapies have sought to eliminate as many tumor cells as possible, the emerging cancer stem cell model suggests that tumors are organized in a hierarchy with a subpopulation of cancer stem cells responsible for tumor initiation, maintenance and progression. Our laboratory is specifically interested in identifying cancer stem cells in different tumors, developing three-dimensional multicellular spheroid tumor models, and exploiting them as cell-based carriers or "Trojan horses" for delivering novel nanotherapeutics and oncolytic viruses. We are also interested in developing mathematical models of cancer stem cell fate and response to therapy.
Targeted nano-therapeutics - Our laboratory uses a unique approach to develop virus-based nanoparticles to target cancer initiating cells commonly known as "cancer stem cells." We examine the effects of tumor microenvironment on cancer stem cell fate and the outcome of newer treatment modalities with virus based and magnetic nano-therapeutics. Learn more
Brain research - The presence of stem cells in the nervous system and their role in tissue homeostasis, injury repair and aging continue to be investigated at length. Our laboratory takes a unique genetic approach to unraveling the mechanism(s) regulating stem cell functions during regeneration following ischemic stroke and traumatic brain injuries. Using gene-targeted and tissue specific knockout mice we aim to better understand how a family of inhibitory proteins called Eph receptors limit the contribution of stem cells to the subsequent remodeling and repair of the neurovascular niche after injury. The overall goal of these studies is to identify effective, safe and feasible drug targets to block these inhibitory signals in order to enhance the therapeutic potential of adult-derived stem cells.
Bioengineered scaffolds - The inflammatory response following brain injury contributes to irreversible tissue loss and often times the formation of an irregularly shaped lesion cavity encapsulated by a glial scar. A potentially powerful approach to restoring function in the area of the cystic cavity is to incorporate a physical support substrate with the capacity to reduce inflammation and promote neovascularization. In collaboration with others on VT campus, we are testing several novel biodegradable Nanofiber matrices for their ability to limit progressive cavitation and jump start tissue regeneration. Learn more