Connect with Us
|
Basic Science Research Center |
||
|
Mission To develop a multi-disciplinary approach to understand how myelin is formed, how it is damaged in disease, and how it may be repaired.
What's going on in Basic Science? The laboratories of Drs. Feltri and Wrabetz, the first two basic science laboratories of the HJKRI, are now fully equipped, functional and host a total of 20 people, including undergraduate and graduate students, post doctoral fellows, senior scientists, technicians and administrators. In Globoid Cell Leukodystrophy/Krabbe disease, deficiency of galactosylceramidase (GALC) causes accumulation of psychosine, the toxic metabolite believed to cause myelin breakdown (demyelination) by killing myelin-forming cells: oligodendrocytes and Schwann cells. Psychosine is also toxic for neurons [1], whose degeneration ultimately causes the signs and symptoms of disease. Whether neurons suffer primarily or as consequence of demyelination, and the exact mechanism of psychosine toxicity are not understood. Other cell types such as blood vessels and immune cells are also present in the nervous system and they have been shown to potentially contribute to disease. For example, macrophages, which in the Krabbe brain are the characteristic globoid cell that gives the disease its name, are probably beneficial [2]. To design effective therapies requires understanding which cells are targeted first by disease and in which cells it is most important to restore GALC function. Dr. Daesung Shin in the HJKRI has generated new GALC transgenes and Dr. Jeff Ceci is using them to generate new mouse models of Krabbe disease in order to address these issues. Clinical studies such as those informed by the World Wide Registry of Krabbe patients and the New York Newborn Screening Program have revealed that Krabbe disease is not only a severe disease of infants, but also manifests with a wide spectrum of severity that includes mild phenotypes with adult onset. The kind of DNA mutation that a patient carries is not always predictive of outcome, and the reasons for such variability—even within the same family—are unclear. This renders the doctor powerless in her or his ability to predict the disease course, with profound implications for treatment options. Understanding why some patients develop milder forms of disease could also suggest a way to reduce disease severity in all patients. To better understand the effect of different mutations and to create new models of disease with various severities, Dr. Daesung Shin has also generated five different disease transgenes carrying GALC mutations characteristic of early or late-onset Krabbe. These resulting transgenic mice should help us to understand factors that determine the outcome and progression of disease, to design rational and effective therapies, and to test them in preclinical trials. Curing Krabbe and other myelin diseases cannot occur without a better overall understanding of myelin and neuronal function in the central and peripheral nervous system. This is why the HJKRI also fosters multidisciplinary research in all aspects of myelination, including the study of oligodendrocyte, Schwann cell and neuronal function. Active projects in the Institute join the understanding of developmental myelination in normal conditions to identification of pathological mechanisms in diseases of peripheral myelin such as Charcot-Marie-Tooth and in syndromic neuropathies. The HJKRI is actively involved in building a critical mass of multidisciplinary investigators to expand the work on myelination and its diseases, and will open calls for the recruitment of 3-4 new primary investigators and their labs in 2012 and 2013. 1. Castelvetri, L.C., et al., Axonopathy is a compounding factor in the pathogenesis of Krabbe disease. Acta neuropathologica, 2011. 122(1): p. 35-48. 2. Kondo, Y., et al., Macrophages counteract demyelination in a mouse model of globoid cell leukodystrophy. J. Neurosci., 2011. 31(10): p. 3610-24. |
Meet the HJKRI
Lawrence Wrabetz, MD
M. Laura Feltri, MD
Caterina Berti
Yannick Poitelon Kathleen Catignas
Monica Ghidinelli
Marilena Palmisano
Domenica Vizzuso
Mariapaola Sidoli Jordan VerPlank Edward Hurley
Courtney Williamson
Nicole Little
Maureen Milligan Amanda Golner Barbara Craft |
|
