Resources
Genise Goldenson Research Fund
A gift from Leonard and Isabelle Goldenson was established to honor their daughter, Genise Goldenson. This Fund was established to support research bearing on cerebral palsy and related neuromuscular conditions with relevance to those factors important to accompanying disorders of mobility.
Current Projects
Chenghua Gu, D.V.M., Ph.D.
Assistant Professor
Department of Neurobiology
Harvard Medical School
Cerebral Palsy (CP) describes a group of disorders of the development of movement and posture that are attribute to non-progressive disturbances that occurred in the developing fetal or infant brain. The incidence of CP is about 2 per 1000 live births, and about 75% of CP occurs during pregnancy. Even though CP is a well-recognized neurodevelopmental condition with motor impairment, our understanding of the etiology and pathogenesis of the disease is very limited. Currently there is no cure for CP and genetic risk factors that may influence severity are unknown. Lack of a basic understanding of the molecular components that determine the wiring of the motor circuitry during development is hampering our progress towards an effective strategy to prevent and treat CP. The goal of the proposed research is to understand the molecular mechanisms governing the development of a major voluntary motor control circuit, the cortical-pontine-cerebellar pathway, in the mouse brain. In this proposal we will focus on the role of a family of repulsive guidance cues, the secreted semaphorins and their receptors in wiring this motor circuit. First, we will characterize the temporal and spatial expression profile of the ligands and receptors in the cortico-Pontine/IO/DCN-cerebellar pathway using immunostaining and imaging techniques. Second, we will address how secreted semaphorins and their receptors may induce the collateral branching and target innervation from the CST by using in vitro co-culture systems. Finally, we will characterize the requirement and cell autonomous function of the receptors and ligands in establishing cortico-Pontine/IO/DCN-cerebellar circuitry formation in vivo using various mouse genetics models we have generated in the lab. We hope increased understanding of developmental neurobiology will provide a foundation to identify structural, genetic risk factors, and other abnormalities in people with CP so that effective preventative and therapeutic strategies can be developed.
Peter B. Kang, M.D.
Assistant Professor of Neurology
Director, Electromyography Laboratory
Children’s Hospital Boston
There are three major categories of muscular dystrophy: (1) X-linked dystrophinopathies, which include Duchenne and Becker muscular dystrophies; (2) limb-girdle muscular dystrophies (LGMDs), which are inherited in autosomal dominant and recessive patterns; and (3) congenital muscular dystrophies, with onset at birth. At least 18 different genes have been linked to the LGMDs. Individually, each LGMD is rare, but collectively they form a major class of inherited myopathies. The candidate has accumulated DNA samples from 16 pedigrees with LGMD, most of which are consanguineous families from Saudi Arabia with a recessive pattern of inheritance. Linkage analysis and homozygosity mapping have been used to screen these kindreds for mutations in known LGMD genes. To date, mutations have been identified in FKRP (4 families), SGCA (3 families), SGCB (3 families), SGCD (1 family), and SGCG (1 family). One family is suspected of having a mutation in CAPN3 or DYSF, and another (the only dominant pedigree) may have a mutation in COL6A1 or COL6A2. Mutation analysis in these two families is ongoing, as well as in the two remaining families who appear to have mutations in novel genes. The lists of candidate genes in these two families are long, and after sequencing a handful of high-yield genes, next-generation high-throughput sequencing and zebrafish knockdown models will be used to screen the many remaining candidate genes. If new causative genes for LGMD are identified, the gene and the protein product will be characterized further. Possible associations with other muscular dystrophy proteins will be explored, as well as functional studies of the protein. New approaches to therapy will be pursued as opportunities arise. The proposed project has the potential to yield tangible and useful scientific knowledge in the study of all muscular dystrophies.
Elio Raviola, M.D., Ph.D.
Bullard Professor of Neurobiology
Department of Neurobiology
Harvard Medical School
We are applying electron microscope (EM) tomography to the visualization of the phototransduction cascade of mouse rod photoreceptors. This technique is based on the principle that the shape of macromolecular assemblies can be reconstructed by algorithms that combine the data from multiple bidimensional views at different projection angles. While EM tomography will provide the spatial resolution (≤1 nanometers) necessary for the visualization of the critical components of the phototrans-duction cascade, instantaneous freezing of retinas either (i) dark adapted or (ii) at known millisecond intervals from termination of illumination will afford the temporal resolution required to catch the dynamic molecular interactions that follow rhodopsin activation and inactivation.
Identification of individual macromolecules will be based on (iii) comparing rods from wildtype mice with those from transgenic animals missing components of the phototransduction cascade and (iv) combining immunolabeling and EM tomography. These experiments represent the first attempt to “see” the components of a signal transduction cascade.
Past Fund Recipients:
Years
awarded |
Name |
Institution |
| 2008-2010 |
Lisa Goodrich |
HMS Neurobiology |