Students & Research
Years shown as of Sept 2012
Thrombospondin-2 in vascular pathology
Thrombospondin 2 (TSP2) is a matricellular protein that modulates cell-matrix interactions and is a potent inhibitor of angiogenesis during tissue repair. Previous studies in TSP2-null mice showed enhanced wound healing, increased angiogenesis, and altered collagen fibrillogenesis suggesting that TSP2 regulates several cellular processes during repair. In addition, preliminary evidence suggests of a potential negative feedback mechanism between TSP2 and nitric oxide (NO). Moreover, there seems to be a correlation between the negative outcome of tissue repair in the presence of low NO levels and the presence of increased TSP2. Interestingly, patients with Diabetes Mellitus type I and II are unable to heal wounds efficiently and this pathology is associated with reduced angiogenesis, altered extracellular matrix (ECM) deposition and remodeling, and a decrease in the levels of NO. The main goal of this project is to investigate the hypothesis that increased TSP2 expression in diabetic wounds, due to low NO levels, contributes to vascular pathology leading to compromised healing.
The Potential Role of E-cadherin during Megakaryocyte and Erythroid Differentiation
E-cadherin is an adhesion molecule with crucial roles in epithelial cell organization, development, and tumorigenesis. However, aside from studies dating back several years that suggest a potential role of E-cadherin in erythropoiesis, its role in hematopoiesis has not been extensively investigated. Given current research supporting non-adhesion functions of E-cadherin as a signaling molecule, and its potential role in promoting actin polymerization, the objective of my thesis project is to elucidate the role of E-cadherin in megakaryopoiesis and erythropoiesis.
Development of Potential Novel Combinatorial Therapies in Malignant Melanoma.
Malignant melanoma is a rapidly increasing public health problem in the United States and in the world, with an increasing incidence of cases as well as decreasing average age of diagnosis. Currently, few treatment options are available for malignant melanoma patients, but, recently, new potential therapeutics have been developed, such as the mutant BRAF inhibitor PLX4032, that target proteins that are specifically oncogenic. For my project, I will explore the effects that some of these targeted agents have on important signaling pathways that are often constitutively activated in melanomas using patient-derived melanoma cell lines. Also, I plan to further elucidate the underlying mechanisms of action behind the therapeutic effects seen with these targeted drugs. Furthermore, my project includes determining potential combinations of drugs that may show some synergistic mechanisms of effect in these melanoma cells.
Hepatitis B virus (HBV) infection, which can lead to chronic hepatitis and hepatocellular carcinoma, is responsible for millions of deaths each year and therefore, is a crucial worldwide public health problem. Although a prophylactic vaccine exists and protects individuals without prior contact with HBV, current therapies are frequently limited in effectiveness by severe side effects and development of viral resistance. Individuals that progress from an acute to chronic HBV infection have a decreased T cell response. While many factors may contribute to this immunological tolerance, it is likely that regulatory T cells (Tregs), a subpopulation of T cells that negatively regulate the immune system, and PD-1/PD-L1 interactions, which regulate the activation, proliferation, and cytokine production of T cells, both play a role. Thus, my project aims to further explore the role of Tregs and PD-1/PD-L1 interactions and to apply this knowledge to the development of a therapeutic vaccination for chronic HBV infection that in overcoming immunological tolerance will stimulate a potent immune response against HBV.
ErbB4 isoform signaling in tumorigenesis
EGFR/ErbB receptor tyrosine kinases are signaling nodes critical in cell growth and development that transduce extracellular signals into a directed cellular response. Members of this receptor family, namely EGFR and ErbB2/HER2/neu, have been shown to be important therapeutic targets in non-small cell lung carcinoma (NSCLC) and breast cancer respectively. Recent data shows ErbB4 mutations are present in certain cancers (e.g., lung, breast, melanoma) but the role of this receptor and its various cleavable isoforms in tumorigenesis is still uncertain. My project will investigate signaling of the four spliced ErbB4 isoforms in cancer and determine if/how particular mutations contribute to tumorigenesis.
The Role of Macrophages in Melanoma Formation and Progression Melanoma
The most deadly form of skin cancer, is characterized by early metastasis and resistance to medical interventions. While much work has focused on the role of recurrent genetic alterations in melanoma biology, the tumor microenvironment may also be instrumental in disease progression. In particular, tumor associated macrophages (TAMs) are thought to support tumor growth and even enhance metastasis. Using novel genetically engineered mouse models of melanoma, my project focuses on deciphering specific mechanisms by which TAMs promote these processes. Additionally, I have begun to identify and characterize TAM sub-populations that may be essential for tumor growth.
Lung adenocarcinoma (ADC) is the most common subtype of lung cancer, and even when diagnosed at early stages, metastases can occur to distant organs. This propensity to metastasize suggests that a subpopulation of malignant cells with high metastatic potential may emerge in a subset of primary tumors. Cancer stem cells have been identified in the lung, but these cell populations are heterogeneous, and although they are all capable of propagating tumors, they display varying degrees of metastatic potential. Previous computational analysis from our lab has shown that genes associated with alveolar differentiation can stratify a cohort of primary lung ADCs into two distinct classes, a differentiated alveolar-like and a stem-cell like class. This stem-like signature classifies patients with poor survival, which indicates it may mark a dedifferentiated cell type that has enhanced metastatic capabilities. My project will focus on identifying biomarkers that are differentially expressed in both the stem-like signature and in our experimental models to identify the origin of metastasis propagating cells in lung ADCs and determine their fate upon disseminating from the primary tumor. I will also determine the putative role of these biomarkers in mediating functional interactions between subpopulations of metastatic cancer stem cells and their microenvironment.
Understanding the Effects of Loss of the Tumor Suppressor Gene, p53 on Mutant EGFR Lung Adenocarcinoma Initiation and Metastatic Progression
Lung cancer continues to be the leading cause of cancer-related death in the US and worldwide. Studies have identified mutations in proto-oncogenes (like the Epidermal Growth Factor Receptor, EGFR) and in tumor suppressor genes (like p53) in lung adenocarcinomas, the most common of the four histological subtypes of lung cancer. In particular, mutations in the EGFR gene have been shown to play a role in tumor initiation and maintenance and we hypothesize that p53 mutations and/or loss contribute to tumor progression. Although more than fifty percent of patients with lung cancer have metastatic disease when they are diagnosed, factors that contribute to the spread of the primary lung adenocarcinoma to distant sites are yet to be well understood. Using mice with mutant EGFR transgenes and constitutive p53 deficiency, the goal of my project is to identify the genes and mechanisms that underlie metastatic spread.