1991 — 2000 |
Maue, Robert Alan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Regulation of Sodium Channel Expression |
0.958 |
2002 — 2004 |
Maue, Robert Alan |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Novel Approaches to Niemann-Pick Type C Disease
DESCRIPTION (Provided By Applicant): Despite recent identification of a gene (npc1) that is mutated in Niemann- Pick Type C (NPC) disease, little is known about the mechanism(s) by which this error leads to the devastating, neurodegenerative changes and childhood neuropathology characteristic of this disorder. We recently provided new insight into the functional implications of this mutation by showing that neurons from the brain of embryonic mice, with NPC disease (npc/nih mice), exhibit not only abnormal cholesterol metabolism, but also deficient morphological and biochemical responses to the neurotrophin, BDNF. In additional experiments, we found that the insensitivity to BDNF stems from a lack of TrkB activation, despite expression of these receptors on the cell surface. Guided by these results, we propose to extend and expand our analysis of this disorder. First, we will define further the nature and extent of the defects in neuronal membrane signaling in NPC disease. We will evaluate the morphological responses to other growth factors, and use cell fractionation and gradient centrifugation to determine if the localization of TrkB and other growth factor receptors to low density, cholesterol-enriched microdomains ("lipid rafts") in the plasma membrane is disrupted in neurons from npc/nih mice. Western blot analysis will also be used to assay the distribution of signaling intermediates often found in lipid rafts, such as Ras and Src, as well as the distribution of the GM1, GM2, and GM3 gangliosides which, in some cases, exhibit altered expression in NPC disease, and in other studies have been shown to be localized to lipid rafts and influence growth factor receptor function. The influence of NPC disease on membrane signaling, through ion channels and synaptic connections, will also be assessed using patch clamp measures of spontaneous activity, evoked activity, and synaptic currents in Purkinje cells in slices of the cerebellum, a region our in situ hybridization studies indicate express high-levels of the npc1 gene. Second, we will test the potential of adenoviral-mediated approaches to retard, halt, or even reverse the neurological deficits observed in NPC disease. To begin, we will determine if viral-mediated expression of an Npc1/GFP fusion protein can restore cholesterol metabolism and BDNF responsiveness to cultured striatal neurons from npc/nih mice. Furthermore, using different modes of infection, including intravenous administration and direct injection into the brain of npc/nih mice, we will assess the extent and duration of Npc1/GFP expression in vivo using confocal microscopic analysis of brain sections, and determine if viral-mediated expression influences aspects of physiology and behavior compromised in NPC disease, including weight, life-span, reproductive capacity, and motor performance. The proposed studies represent novel ideas and approaches with regard to NPC disease, and will both increase our understanding of the neurological deficits that occur and explore a potential therapeutic strategy for what is, at present, an incurable disorder.
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0.958 |
2015 |
Maue, Robert A. |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Alterations and Renovations
An overall mission of NH-INBRE is to increase the amount and sophistication of biomedical research occurring at institutions of higher learning in New Hampshire. A key step in accomplishing this is to increase the existing research infrastructure in the form of modern laboratory space. In the inaugural phase of the NH-INBRE the mechanism for alterations and renovations was used to create two small research laboratories at one of our Partner institutions. This was very successful, as the labs have been used by what have become two of our most active new NH-INBRE investigators, as well as the large cadre of student researchers they have included in their research efforts over the past 4 years. Building upon this successful model, we now propose to create and upgrade laboratory space at three of our Partner institutions ? Franklin Pierce University, New England College, and St Anselm College. Plans were developed and selected in an open, competitive process that included donated time and effort from Dartmouth Facilities Office personnel and experienced professional contractors. When completed, the proposed renovations will lead to marked increases in the number of faculty who can have a role as active investigators and an increase in the number of student researchers at these Partners, as well as an increase the research capabilities and resources at these INBRE institutions. On a broader scale, they will make significant contributions to the development of a vibrant and visible research culture at these schools.
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0.958 |