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Eleven individuals were awarded fellowships or grants at the CAF Board meeting on June 30
by Craig Butler |
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August 7, 2007- Funding medical research is one of CAF’s biggest priorities, with CAF awarding $540,000 in this area this year. Our medical research fellowship program has been encouraging and assisting promising researchers for decades; more recently, our grants for translational research in adult thalassemia have allowed us to expand into new areas of concern to the thalassemia community.
The medical research fellowships are awarded to post doctoral and junior faculty members investigating clinical or basic research related to thalassemia. Each fellowship carries an annual stipend of $40,000 and is awarded for one year, with the possibility of renewal for a second year. Translational research grants are awarded to junior and senior faculty who interact directly with patients or patient-related data. Each grant carries an annual stipend of $60,000 and is awarded for one year, with the possibility of renewal for a second year. At its annual Board meeting on June 30, 2007, CAF awarded five first-year and four renewal medical research fellowships and two grants in translational research. CAF is also currently funding the second year of its initial translational research grant. The renewal grant in translational research was awarded to: Zhiyue Jerry Wang, MD, Baylor College of Medicine, Houston, "Quantification of Cardiac Iron Concentration in Cooley's Anemia by MRI Susceptometry" First year grants in translational research were awarded to: Sylvia T. Singer, MD, Children’s Hospital and Research Center, Oakland, “Fertility in Females with Thalassemia Major: Determination of Reproductive Status and Relation to Iron Overload” Recipients of renewal fellowships for 2007-2008 include: Quan Zhao, PhD, Bone Marrow Research Laboratories, Melbourne Health Research Directorate, “The Role of Protein Methyltransferase 5 (PRMT5) in Fetal Globin Gene Silencing” Recipients of first year fellowships include: Faith Harrow, PhD, National Human Genome Research Institute, “Novel vectors for Cooley’s Anemia Gene Therapy Using Globin Regulatory Elements” CAF congratulates all of these recipients and thanks them for their commitment to thalassemia research. Information About Recipients and Projects This section is in progress. Zhiyue Jerry Wang Description of Research The leading cause of death for thalassemia patients receiving long-term blood transfusion therapy is cardiac failure. Patients with cardiomyopathy, caused by cardiac iron overload, can be treated with intensive iron chelation therapy. However, prevention of cardiac iron overload would need precise measurement of cardiac iron concentration (CIC), especially as already relatively low CIC values may cause cardiac tissue damage. Currently, it is not clear if long-term low liver iron concentration is sufficient to prevent patients from accumulating iron in the heart. Moreover, iron depletion in response to chelating treatment may differ in liver and heart. It is therefore important to utilize a direct measurement of CIC in guiding the life-saving chelating therapy. The assessment of T2* by MRI has become a widely used method for evaluating cardiac iron overload. Although T2* is a very sensitive method for any magnetic susceptibility gradient (including iron), it is simultaneously susceptible to various perturbations and calibration will become difficult. We propose to develop cardiac iron susceptometry by MRI for directly measuring the magnetic susceptibility of the heart, in a conceptually similar way as SQUID for the liver. First test measurements seem to be very promising. This will be a collaborative project between Texas Children’s Hospital and Children’s Hospital & Research Center at Oakland. The project will provide preliminary results for an NIH grant application for a larger scale patient study. Eventually, MRI cardio-susceptometry will help establish the relationship between T2* and the cardiac iron concentration.  Sylvia Singer
Biography As a Hematology/Onclogy physician at CHRCO, I have centered my career interests over the past seven years on thalassemia, at both a clinical and a research level. Working with an internationally recognized expert in pediatric hematology, Dr. Elliott Vichinsky, I have been able to combine my clinical efforts and research interests on this prevalent and complex disease. My first project involved investigating the frequency of alloimmunization and autoimmune hemolytic anemia in chronically transfused thalassemia patients. I then moved to coordinate the NIH funded study on a significant, yet under-recognized type of thalassemia: Hemoglobin E/beta-thalassemia (RO1 HL-97-013) from 1998-2003. Currently I am funded to investigate the risk factors for developing pulmonary hypertension in thalassemia (1 K23 HL077409-01A1). By integrating basic science in coagulation/inflammation with clinically significant complications in thalassemia, I hope to contribute to this field and to improve the outcome of thalassemia patients. My short term goals include continuing to investigate this topic and identifying markers for developing a larger randomized study for identifying and treating hypercoagulable problems and pulmonary hypertension in thalassemia. My future goals continue to center around developing a career in clinical and translational research of thalassemia. I actively participate in the thalassemia clinics and am mostly interested in addressing and developing research centered on clinical problems that affect patients. Through my current research, I expect to transition into an independent clinical investigator and to be able to execute such studies. Description of Research Infertility and early menopause are among the most difficult issues for adult females with thalassemia major, who are now living longer lives. Newer tests to assess the chances of women getting pregnant are now available, but have not yet been tested in thalassemia females. These include blood tests and a special ultrasound of the ovaries. In this study, we propose to use these methods with 16-18 adult thalassemia major females in order to be able to predict their chances for pregnancy and determine their fertility status. We would then assess how the level of iron overload and toxic effects of iron are related to their fertility. This could provide a better understanding of the reasons for, and the timing in which, this damage to the reproductive system occurs. With further study, these methods could become an important way to find out fertility status and how it relates to the level of iron overload. It may lead to earlier treatment intervention for preserving fertility, which can have a profound impact on patients' quality of life.  John Wood
Biography Dr. John Wood graduated from UC Davis (Electrical Engineering) in 1984 and received his MD/PhD (Bioengineering) from the University of Michigan in 1994. He performed his residency and fellowship in Pediatric Cardiology at Yale and joined Children’s Hospital Los Angeles/USC Keck School of Medicine in 1999. Dr. Wood is the director of cardiovascular MRI and specializes in the MRI assessment of congenital heart disease, as well as noninvasive assessment of iron burden by MRI. Dr. Wood has been studying the cardiovascular consequences of hemoglobinopathies for almost a decade. He is one of the pioneers of MRI-based cardiac and liver iron measurements but is also studying oral chelation strategies in animals and humans. He is the principle investigator for the NIH-sponsored Early Detection of Iron Cardiomyopathy Trial, which is trying to identify earlier markers of cardiac dysfunction. Dr. Wood has recently begun studying the relationship between pancreatic iron burden by MRI and their functional correlates. Description of Research Diabetes is common in thalassemia major and becoming more important as patients live longer. Standard patient monitoring for diabetes detects disease only once it is fairly advanced and not completely correctable. We believe that magnetic resonance imaging (MRI) can be used to detect iron in the pancreas before irreversible damage is present and can be used to guide iron removal therapies. This study will examine the relationship between MRI detectable iron in the pancreas and liver with tests of pancreas function and sugar metabolism in thalassemia patients. Quan Zhao Biography Dr. Quan Zhao from the Bone Marrow Research Laboratories (BMRL), Royal Melbourne Hospital, Australia, received his Bachelors Degree from Nanjing University, China, in 1988. He worked in immunology in Jinling Hospital until moving to Australia in 1998, where he subsequently completed a PhD at Latrobe University in Melbourne in 2001 in the field of mitochondrial biogenesis. Since then, he has worked at the BMRL examining the complex transcriptional control of the human gamma globin genes, with the aim of translating his findings into clinical applications for Cooley's anemia and sickle cell anemia. He has published over 20 papers in journals that include EMBO Journal and Blood, five of which relate to blood and hemoglobin production. He is currently a Senior Research Fellow. Description of Research Hemoglobin is the major protein in the human red blood cells and is essential for the transport of oxygen from the lungs to the tissues. The disorders of hemoglobin production, collectively known as the hemoglobinopathies, are the most common genetic diseases worldwide, affecting approximately 10% of the global population. Two of these disorders, beta thalassemia and sickle cell anemia, are particularly devastating. Patients with beta thalassemia fail to produce normal adult hemoglobin and require regular blood transfusions and iron chelation therapy for life. Patients with sickle cell anemia produce abnormal hemoglobin which is insoluble and prevents red blood cells from passing through the microcirculation. These children suffer from painful crises due to blocked vessels, culminating in stroke, blindness, kidney failure and irreversible damage to a range of other organs. Both these diseases can be markedly improved with elevation of the form of hemoglobin produced by the developing embryo, fetal hemoglobin. Dr. Zhao's research focuses on understanding how the fetal globin genes are regulated, with a view to reprogramming them into activity in adults with Cooley's anemia and sickle cell anemia. He has identified key factors important for fetal gene expression and is currently characterizing the mechanisms by which they achieve this effect. His goal is to translate these findings into therapies for the hemoglobinopathies.  Janelle Keys
Biography I completed my undergrad and graduate work at the University of Sydney, Australia. I then spent six years working at Duke University, North Carolina, before returning home in 2004 to take up a position at the University of Queensland. My research at UQ is focused on blood diseases like Cooley’s anemia. Description of Research Cooley’s anemia is a fatal genetic blood disease that is characterized by failure to produce the oxygen carrying molecule hemoglobin in adult red blood cells. Patients develop normally due to the presence of hemoglobin that is produced specifically in the fetus. Importantly, we know that if we can reactive expression of fetal hemoglobin during adulthood, then the symptoms of the disease are abated. Hemoglobin expression is controlled by many different proteins, and one of these is termed "Ikaros." The aim of this project is to define how Ikaros works to alter the levels of both fetal and adult hemoglobin. This knowledge may then be useful in developing novel treatments for the reactivation of fetal hemoglobin, thereby curing Cooley’s anemia. Xiaomei Wang Biography (In progress.) Description of Research Hemoglobin, the blood oxygen carrier, is made up of two proteins, termed alpha (α) and beta (β) hemoglobin (Hb). Cooley’s anemia (β thalassemia) is caused by mutations that impair the synthesis of βHb. Consequently, there is a buildup of free αHb, which is extremely toxic to red blood cells. It is believed that the accumulation of excess free αHb is responsible for many clinical problems associated with Cooley’s anemia. Our laboratory discovered alpha hemoglobin stabilizing protein (AHSP), a protein that binds free αHb and blocks its damaging effects. We showed that in mice, loss of AHSP worsens β thalassemia. Here we propose to study further the role of AHSP in β thalassemia using two approaches. First, we will study several AHSP mutations to learn more about how the protein functions. This includes a naturally occurring human AHSP mutation that is associated with unexpectedly severe β thalassemia in two families. Second, we will investigate whether genetic manipulation to increase AHSP levels in red blood cells can alleviate some symptoms of β thalassemia. These studies will improve our medical understanding of Cooley’s anemia. In addition, our work could pave the way for new treatments that are based on neutralizing noxious αHb using drugs that mimic AHSP.  Thomas Benedict Bartnikas
Biography Originally hailing from Canada, I attended Cornell University in Ithaca, New York, where I obtained my undergraduate degree in biology. I then headed westward to St. Louis, Missouri, for the MD/PhD program at Washington University, where I studied Lou Gehrig’s disease and copper metabolism with Jonathan Gitlin. Eager to return to colder climates, I made my way to Boston for a pediatric internship at Children’s Hospital in Boston, Massachusetts. I am currently working as a basic science postdoctoral fellow in Nancy Andrews’ laboratory at Children’s Hospital where I am studying the regulation of hepcidin expression and its role in beta-thalassemia. Description of Research My fellowship research focuses on understanding iron overload in beta-thalassemia. Most of the iron in the human body is used to make red blood cells; this process, known as erythropoiesis, occurs in the bone marrow. In beta-thalassemia, the production of red blood cells is impaired and the iron intended for red blood cells is absorbed by other tissues. At high levels iron is toxic and can damage organs such as the heart. The body attempts to compensate for the lack of red blood cells by absorbing more iron from the diet, despite the fact that the body already has more than adequate levels of iron. The absorption of dietary iron into the bloodstream is controlled by hepcidin, a molecule made by the liver. We hypothesize that the bone marrow influences the absorption of dietary iron by making molecules that circulate through the bloodstream and alter the liver’s production of hepcidin. We are currently searching for such molecules. Understanding how the bone marrow controls iron absorption from the diet may allow us to limit the iron overload seen in beta-thalassemia.  Faith Harrow
Biography I received my Ph.D. in molecular biology from the City University of New York in 2005, under the mentorship of Dr. Benjamin Ortiz. As a graduate student, I studied mechanisms that regulate developmental and tissue-specific patterns of gene expression in T-lymphocytes. An understanding of the activities of the DNA elements involved in these mechanisms may be applied to gene therapy studies currently underway for congenital immune disorders, leukemia and HIV/AIDS. I am now a postdoctoral fellow in the lab of Dr. David Bodine at the National Human Genome Research Institute of the NIH. One of our research objectives is to design safe gene therapy vectors that express therapeutic levels of β-like globin, which may be used to treat human hemoglobin disorders such as Cooley’s anemia. Our novel approach makes use of erythroid-specific promoters capable of driving high-level globin expression independent of enhancer elements, a strategy that minimizes the risk of oncogene activation upon proviral integration. Description of Research Patients with Cooley’s anemia have a lifelong anemia that is the result of their having fewer than the normal number of red blood cells. In addition, the few red cells that patients do make contain lower amounts of hemoglobin, the protein that carries oxygen throughout the body. The decreased hemoglobin content and red cell number of Cooley’s anemia patients is due to having inherited a non-functional β-globin gene or genes from their parents. Severe Cooley’s anemia can be fatal if left untreated. All of a person’s red blood cells come from a few immortal cells in the bone marrow (known as hematopoietic – or blood forming stem cells). Transplantation of stem cells from a healthy person can potentially cure Cooley ’s anemia. However, like heart or kidney transplant recipients, many patients will reject the new marrow unless the donor is a very close match. Unfortunately, very few Cooley’s anemia patients have a suitable donor for a bone marrow transplant. Gene therapy is an experimental therapy in which a healthy beta-globin gene can be inserted into a patient’s own stem cells (which would not be rejected) using a virus. Gene therapy has been successfully used to cure more than 20 patients with immune deficiency, but in 4 of those patients the insertion of the virus caused a leukemia gene to become active. Although 3 of the 4 patients were successfully treated for the leukemia, this risk is too high. The current versions of globin gene therapy viruses include DNA sequences, called “enhancer elements,” that are powerful activators of nearby genes, which may increase the risk of leukemia. We have engineered a new virus that eliminates all enhancer elements and can make enough β-globin to cure Cooley’s anemia. Experiments that test our new virus in mice with Cooley’s anemia and in cells from Cooley’s anemia patients will determine whether our improved design can be developed to cure Cooley’s anemia without the risk of leukemia seen in the immune deficiency patients.  Seigo Hatada
Biography Seigo Hatada received his PhD from the University of Tokyo in 1996. He began his association with the University of North Carolina at Chapel Hill shortly thereafter, first as a postdoctoral fellow and subsequently as a postdoctoral research associate and currently as a research assistant professor in the department of pathology and laboratory medicine. He also has served as an assistant professor in the department of regenerative medicine at Toho University. Description of Research Most defects that cause Cooley's anemia are mistakes in genes that control the production of the hemoglobin in red blood cells. An established method of treating severe forms of this anemia is to replace the defective stem cells in the patient's bone marrow with transplanted stem cells from a normal donor. This can be successful, but there are substantial problems in finding suitably matched donors and in avoiding immunological reactions between the cells of the donor and those of the recipient. My proposed work is aimed at developing a gene correction procedure that may eventually allow stem cells to be obtained directly from the patient for correction of the faulty gene, followed by return of the now corrected cells to the patient. This procedure would remove the difficulty of finding a donor and would eliminate the problems of immune reactions. I propose to develop and test a gene correction procedure of this type by using an existing mouse model of thalassemia. From these mice, I will isolate a type of bone marrow cell that I can culture outside the body and will correct the faulty hemoglobin gene in the cultured cells by a novel method of gene targeting that I have developed. (Gene targeting can use normal DNA to correct a faulty gene.) Although my proposed work will be with mice, I expect that it will make a substantial contribution toward the future development of a similar procedure to improve the condition of human patients with Cooley's anemia.  Michela Battista
Biography In 2001, graduated from the University of Genova in Italy, where I studied the expression and the regulation of the β-subunit of the voltage dependent sodium channel. I then moved to New York, where I worked as a research associate in Michael Lisanti's laboratory at Albert Einstein School of Medicine. During my work in Dr. Lisanti's laboratory, I characterized the role of the lipid rafts marker caveolin-1 in bone formation. Additionally, using a deletion mutagenesis approach, I evaluated the contribution of the unconserved N- and C-terminal domains of caveolin-1 and -2 to their subcellular distribution and their role in caveolar biogensis. My interest in hematopoietic stem cell trafficking began when I joined Paul Frenette's laboratory in June, 2004. Under Dr. Frenette's guidance, I explored a great diversity of body systems such as the hematopoietic, skeletal and nervous systems. Some of this research demonstrated in a novel way the link between the sympathetic nervous system and hematopoietic stem cells, and was published in January 2006 in Cell. Description of Research Cooley's anemia is a disease of red blood cells that can be managed by blood transfusion therapy but cannot yet be cured. Bone marrow transplantation (BMT) is currently being pursued as the most promising curative treatment for patients living with Cooley's anemia. In order to harvest blood-forming stem cells (hematopoietic stem cells, HSCs) for BMT, a drug called granulocyte colony stimulating factor (G-CSF) is given to donors to elicit mobilization of those cells from their normal site of residence, the bone marrow, into the peripheral circulation, where they can be easily accessed. Although this harvesting strategy is preferred over the older method of bone marrow aspiration because of improved efficacy for the recipient and safety for the donor, G-CSF-induced HSC mobilization response can vary widely from person to person and sometimes fails to elicit sufficient numbers of HSCs. Our previous work shows that the sympathetic nervous system contributes significantly to HSC mobilization. We have already demonstrated that G-CSF depletes catecholamine (neurotransmitters found in the sympathetic nervous system) levels in the bone and are actively investigating the molecular mechanisms for this depletion. The sympathetic nervous system represents a potential target for future therapeutics that may complement G-CSF in its actions, reduce variability in donor response and provide mechanistic insight on how HSC mobilization works on a systemic level, ultimately leading to imprvoements in the quality of life for those suffering from thalassemia.  Rajasekhar NVS Suragani
Biography I did my Bachelor's from Osmania University, India, specializing in Microbiology, Genetics and Chemistry (1994). I then completed my Master's in Biotechnology (1999) from Nagarjuna University, India, and carried out the dissertation work for the Master’s degree at the Bhabha Atomic Research Centre (BARC), Mumbai, India. I then joined the Dept. of Biochemistry, University of Hyderabad, India, for the doctoral studies under the guidance of Prof. K.V.A. Ramaiah. I expressed and characterized the recombinant human translational initiation factor 2 (wild type and its mutant subunits) for the inter-subunit, inter-protein and ligand interactions. I received my Doctoral degree in 2005. I later joined for postdoctoral studies in Dr. Jane-Jane Chen’s laboratory at Harvard-MIT Division, Massachusetts Institute of Technology, Cambridge, MA, in November, 2005. The long term objectives of Dr. Chen’s laboratory are to contribute to the understanding of the molecular mechanisms involved in the pathology of red blood disorders with hemoglobinopathies and to discover novel pharmaceutical treatments for these diseases. They focus on the regulation of protein synthesis in erythroid cells mediated by Heme Regulated Inhibitor eIF2α kinase (HRI) in heme deficiency and under normal and stress erythropoiesis. HRI senses heme availability to regulate globin synthesis in erythroid cells. It also protects erythroid cells from heat shock, osmotic and oxidative stress. HRI is activated in heme-deficiency and other cellular stresses by autophosphorylation and phosphorylates the α-subunit of eIF2 and inhibits global protein synthesis. Description of Research Most recently, Dr. Chen’s group discovered the role of HRI in decreasing the severity of β-thalassemia. In fact, HRI is a significant modifier, identified so far in mouse models of β-thalassemia. HRI is normally activated in erythroid cells of β-thalassemic mice to decrease α-globin and decreases apoptosis of erythroid precursors. The double knock out (Hri-/-Hbb-/-) mice die of severe anemia by 18th day of embryonic stage. In addition to inhibiting general translation, activation of HRI leads to induction of gene expression necessary for adaptation of stress conditions termed HRI signaling pathway. The steady state of phosphorylated eIF2α (eIF2αP) in vivo is maintained by the equilibrium of eIF2α kinase and eIF2αP phosphatase. Recently, a small chemical, salubrinal, was discovered as a selective inhibitor for the dephosphorylation of eIF2αP under endoplasmic reticulum stress. Thus, salubrinal might increase eIF2αP in erythroid precursors and reduce severity of β-thalassemia, similarly to the activation of HRI. I will test and evaluate this hypothesis in mouse beta-thalassemic red cell precursors. I will also elucidate the HRI signaling pathway under oxidative stress and screen for novel small chemical compounds that would protect erythroid cells against oxidative stress. These studies will provide further insights to the action of HRI in protecting β-thalassemia and may also have the potential for novel treatments of thalassemic patients.  Hiromi Gunshin
Biography Hiromi Gunshin joined the School of Public Health and Health Sciences, Department of Nutrition at the University of Massachusetts in Amherst in September 2006. Gunshin received her Ph.D. in Nutritional Biochemistry from the University of Tokyo. She worked as a Research Fellow at Brigham and Women's Hospital with Dr. Matthias Hediger and at Children's Hospital Boston with Dr. Nancy Andrews at Harvard Medical School. She pursues her research interests to understand the mechanisms of metal-ion transport in health and disease. Description of Research Patients with thalassemia cannot produce healthy blood cells. Repetitive red blood cell transfusions and upregulated iron absorption lead to a condition known as iron overload. Excess iron is toxic to human organs, particularly the liver and heart. The excess iron must be removed mostly by invasive chelation therapy. Alternative therapies, therefore, will ultimately increase the quality of life for thalassemia patients. To achieve this goal, I propose to examine the molecular and cellular mechanisms involved in iron absorption leading to iron overload in the liver and heart. |
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| Cooley's Anemia Foundation, Inc. TEL: 800 522-7222 FAX: 212 279-5999 info@cooleysanemia.org | ||||||
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