Hunter James Kelly Research Institute -
To develop a multi-disciplinary approach to understand how myelin is formed, how
it is damaged in disease, and how it may be repaired.
- To study myelin formation as a source for strategies of myelin repair
- To study consequences of myelin damage—common to all diseases of myelin— such as inflammation or neurodegeneration which correlates best with disability (symptoms and problems of daily living)
- To provide better cellular and animal models (cell based assays, transgenic mice or fish) for identifying mechanisms of disease
- To exploit models to perform preclinical studies of therapies
- To translate the research of HJKRI into prognostic, diagnostic treatment applications in cooperation
with the University at Buffalo Department of Neurology and Hunter’s Hope Foundation
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 , 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 . 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
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):
Laboratories focused on Myelin Repair
Professor of Biochemistry, University at Buffalo
M. Laura Feltri, MD
Our research focuses on adhesion and signaling molecules that mediate
contact between myelinating cells and axons or the extracellular matrix.
One of our major efforts has been the study of laminin receptors on
Schwann cells, the myelinating peripheral glia.
Since our arrival at the HJKRI we are also applying our experience on
conditional mutagenesis to ask if there is cell autonomy in the
pathogenesis of Krabbe disease.
Director, HJKRI & Professor of Neurology, University at Buffalo
Lawrence Wrabetz, MD
The Wrabetz Laboratory is interested in the molecular genetics of myelination.
Translating past experiences, this lab now focuses on the
generation of new mouse models of Krabbe disease that carry authentic
GalC mutations found in patients with diverse clinical phenotypes. These
animal models will provide insight into the effect of different
mutations on the function of the galactosylceramidase protein and on the
pathogenesis of the disease.