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ROLE OF NGF IN FAMILIAL DYSAUTONOMIA

Award Number: R01NS061842
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: 04/01/2008
PERIOD OF PERFORMANCE END DATE: 03/31/2014

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ROLE OF NGF IN FAMILIAL DYSAUTONOMIA - DESCRIPTION (provided by applicant): Despite evidence that neurotrophins play an essential role in the development and maintenance of the peripheral nervous system, the mechanisms underlying neurotrophic dysfunction in different human peripheral neuropathies as well as its relevance to the disease process are still not well defined. Familial Dysautonomia (FD) is the most frequent hereditary autonomic and sensory neuropathy. Individuals affected with FD display dysfunction of the peripheral nervous system already at birth accompanied by abnormally low numbers of neurons in sympathetic and sensory ganglia. The disorder is caused by mutations in the gene Ikbkap, which encodes IKAP. With the identification of the gene that causes FD, the mechanisms underlying the disease can now be more clearly delineated. We have generated a mouse model for FD by mutating the mouse Ikbkap gene homolog. To date this is the only model that recapitulates the molecular and pathological features of the disease and thus represents an invaluable and unique tool to determine the mechanisms underlying the disease neuropathology. Based on our preliminary results, the findings that neurotrophic activity is reduced in serum and fibroblasts from FD patients, that IKAP regulates expression of furin (the enzyme required for NGF processing in embryogenesis), and that inhibition of NGF activity recapitulates the disease neuropathology in vivo, we hypothesize that reduced NGF-mediated neurotrophic support underlies FD neuropathology. Using molecular, biochemical, cellular, and genetic approaches we will (1) test the hypothesis that transcriptional regulation of NGF is impaired in our model of FD, (2) test the hypothesis that the reduced biological activity of NGF in our FD mouse model is due to impaired pro-NGF processing and signaling, (3) test the hypothesis that over-expression of NGF and/or furin rescues neuronal cell loss in the developing peripheral nervous system of FD mice. The analyses proposed will not only provide further information into mechanisms underlying FD, but also insight for potential therapeutic intervention. Also it will enhance our understanding of the normal peripheral nervous system development and maintenance. PUBLIC HEALTH RELEVANCE: Peripheral neuropathies affect a significant fraction of the population and are classified as inflammatory, toxic, metabolic (diabetes mellitus) and hereditary neuropathies. Familial Dysautonomia (FD) is the most frequent hereditary neuropathy, and is inevitably fatal. Understanding the mechanisms underlying this disorder will provide insights for potential new therapeutic interventions for FD and for other peripheral nervous system disorders.


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: 2013 ( Subtotal = $0 )
2013	2011	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	4	3/27/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $312,988 )
2011	2011	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	4	6/8/2011	NON-COMPETING CONTINUATION	$25,550
2011	2011	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	4	2/23/2011	NON-COMPETING CONTINUATION	$287,438
														Subtotal = $312,988

Issue Date FY: 2010 ( Subtotal = $316,182 )
2010	2010	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	3	3/12/2010	NON-COMPETING CONTINUATION	$316,182
														Subtotal = $316,182

Issue Date FY: 2009 ( Subtotal = $319,375 )
2009	2009	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	002	2	3/25/2009	NON-COMPETING CONTINUATION	$319,375
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	1	12/17/2008	NEW	-$319,375
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	1	12/24/2008	NEW	$319,375
														Subtotal = $319,375

Issue Date FY: 2008 ( Subtotal = $319,375 )
2008	2008	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/24/2008	NEW	$319,375
														Subtotal = $319,375

Grand Total All Awards = $1,267,920

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ROLE OF NGF IN FAMILIAL DYSAUTONOMIA

Award Number: R01NS061842

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: 04/01/2008

PERIOD OF PERFORMANCE END DATE: 03/31/2014

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