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NEUROPATHOLOGY AND PATHOGENESIS OF HUNTINGTON'S DISEASE

Award Number: R56NS028721
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/1990
PERIOD OF PERFORMANCE END DATE: 08/31/2010

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NEUROPATHOLOGY AND PATHOGENESIS OF HUNTINGTON'S DISEASE - Huntington¿s disease (HD) is a hereditary neurodegenerative disorder that results in a progressive decline in cognitive ability due to an early occurring dysfunction in cerebral cortex and a progressive decline in motor control due to the steady loss of striatal projection neurons from the basal ganglia. While the mutated huntingtin protein (Htt) that underlies HD pathogenesis appears to interfere with a wide array of cellular functions, the means by which mutant Htt brings about the cortical and striatal pathology of HD remains uncertain. Several lines of evidence suggest that the Htt mutation causes a reduction in BDNF (brain-derived neurotrophic factor) production and transport by corticostriatal neurons, resulting in deprivation of striatal neurons of this vital trophic factor, and that this may be the major means by which HD destroys striatal projection neurons. It is unknown, however, if the striatal pathology caused by BDNF deprivation is truly HD-like, and it is unknown if the HD mutation initiates a striatal injury process that is mediated by a deficit in pro-survival BDNF signaling. The present proposal seeks to address these two issues to more firmly establish if BDNF deprivation plays a significant role in the striatal injury process in HD. If shown to be implicated, BDNF replacement therapy would then be a viable approach for combating striatal injury in HD, for example by means of striatal implant of stem cells engineered to produce BDNF. Moreover, if the cerebral cortex is identified by our studies as the primary site at which the mutation acts to bring about indirect striatal injury, our findings would guide therapies seeking to reduce mutant protein expression to target cortex. Four lines of study will be carried out, each to address a key question related to the hypothesis that striatal deprivation of cortically produced BDNF underlies striatal injury in HD. Aim 1. Are the localization of BDNF in corticostriatal neurons and its receptor trkB in striatal projection neurons in normal animals consistent with the differential vulnerability among striatal projection neurons in HD? Aim 2. Is the vulnerability of striatal projection neurons to BDNF deprivation consistent with their differential vulnerability in HD? Aim 3. What intracellular signaling pathways mediate the deleterious effects of BDNF deprivation on striatal projection neurons? Aim 4. Does the HD mutation cause injury to striatal projection neurons via the intracellular signaling pathways used by BDNF deprivation? The studies will employ mutant mouse models of HD and cortex-specific knockout of BDNF expression, and in vitro approaches.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2009 ( Subtotal = $0 )
2009	2008	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	15	11/21/2008	COMPETING CONTINUATION	$321,927
2009	2008	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	11/18/2008	COMPETING CONTINUATION	-$321,927
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $321,927 )
2008	2008	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	7/23/2008	COMPETING CONTINUATION	$321,927
														Subtotal = $321,927

Grand Total All Awards = $321,927

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NEUROPATHOLOGY AND PATHOGENESIS OF HUNTINGTON'S DISEASE

Award Number: R56NS028721

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/15/1990

PERIOD OF PERFORMANCE END DATE: 08/31/2010

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