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Robert Grady, PhD and Patricia Giardina, MD continue their collaboration on the development of new orally effective compounds which can promote iron excretion in iron overloaded thalassemia patients. The accumulation of iron in tissues remains a major cause of morbidity in patients with congenital hemoglobinopathies that require frequent blood transfusions. The cornerstone of successful iron chelation therapy in these patients has been desferrioxamine (DFO). DFO is effective only when administered subcutaneously. This route of administration has been a major reason for noncompliance among children and adolescents requiring this therapy. This issue is currently being addressed by developing agents that can be given by mouth that have similar safety and efficacy profiles to DFO.
Susanna Cunningham-Rundles, PhD's research is focused on the molecular development of the human cellular immune response and how this may be modulated by microbial encounter. Specific projects center on mononuclear cell effector response as mediated by monokine and cytokine patterns of production and secretion. The objective is to analyze the fundamental basis of functional expression of T cells and Natural Killer (NK) cells. Representative projects include: signaling and activation of the interferon system, development of immunity in congenital HIV infection, cytokine response to synthetic HIV peptides and antioxidant and non-antioxidant micronutrient modulation of immune response.
David C. Lyden, MD, PhD and his research team are examining the "microenvironment" of the metastic site – the enzymes, proteins, and growth factors that encourage cancer's spread. They have identified a type of stem/progenitor cell originating in the bone marrow, called vascular endothelial growth factor receptor 1+ (VEGRF1+) cells. These cells are found in extremely small numbers in the bone marrow, and usually remain dormant until "awakened" by specific chemicals called growth factors. In the case of VEGFR1+ cells, it was observed that growth factors released by primary cancers triggered this awakening. As tumor-exuded growth factors circulated in the bloodstream, VEGFR1+ cells began to cluster together, moving out of the marrow and settling in specific sites in various organs. These sites were found to be the same as those that are eventually occupied by metastatic cancer cells that spread from the primary tumor.
Dr. Lyden's team also discovered that fibronectin – a protein secreted naturally by cells called fibroblasts – acts as a kind of "glue," helping VEGFR1+ cells settle in the "pre-metastatic niche." This partnership of cells and proteins creates the ideal environment for migrating cancer cells, in exactly the location they are seeking depending on their specific cancer type.
In addition to helping identify individuals who may need preventive therapies to reduce their chance of metastatic disease, this groundbreaking work could eventually lead to methods of preventing primary cancers from spreading.
Stefano Rivella, PhD's research is focused on ways of allowing healthy genes to be successfully transferred into hematopoietic stem cells using lentivirus-based gene transfer, leading to a cure for thalassemia and other hematological diseases. For this reason a lentiviral vector, named TNS9, was generated. This vector carries the entire human β-globin gene along with its promoter, enhancers, and distal genetic elements. Mice that suffer from the most severe form of β-thalassemia major have been rescued by stem cells transduced with TNS9 to carry a normal version of the human beta-globin gene. Currently, new genetic approaches and new pharmacological therapies are proposed for the cure of β-thalassemia, and studies are being performed to evaluate the best genetic and pharmacological treatments. Other projects include the generation and evaluation of new lentiviral vectors using genomic elements that prevent silencing, position effects, and insertional mutagenesis.
Other projects include the generation and evaluation of new lentiviral vectors using genomic elements that prevent silencing, position effects, and insertional mutagenesis.
In order to fully understand the physiology and molecular mechanisms that occur in beta thalassemia, new mouse models are also being developed to study globin gene regulation, ineffective erythropoiesis and iron uptake.