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BIOCHEM. BASIS OF AXONAL & MYELIN INJURY IN HEAD TRAUMA

Award Number: R01NS049175
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: 05/01/2005
PERIOD OF PERFORMANCE END DATE: 04/30/2009

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BIOCHEM. BASIS OF AXONAL & MYELIN INJURY IN HEAD TRAUMA - DESCRIPTION (provided by applicant): A considerable amount of traumatic brain injury (TBI) research has focused on the pathologic significance of mechanical and chemical insults (e.g. disturbed calcium homeostasis) to the axons. Yet the precise biochemical mechanisms of axonal injury remain unclear. White matter loss and demyelination have been insufficiently studied in TBI, and we have little knowledge of the biochemical mechanisms of myelin damage. In the past, our laboratories and others have documented over-expression and activation of various proteases (e.g. calpains, caspases, and matrix metalloproteases) following brain injury. In this proposed research, we hypothesize that a subset of structural proteins in axons and myelin are differentially vulnerable to proteolysis after TBI. Inevitably, such proteolysis would result in degradation that significantly compromises the structural and functional integrity of axons and myelin sheaths leading to long-lasting axonal damage and demyelination. The proposed research represents the first systematic examination of the mechanisms of proteolvtic degradation of structural proteins in both axons and mvelin. Our preliminary data have already identified several axonally-enriched proteins that are vulnerable to proteolysis (neurofilament- H, and -L, microtubule-associated protein tau, axolemma-associated amyloid precursor protein [APR] and cytoskeletal proteins alphall- and (betaII-spectrin). Importantly, we have also identified at least two myelin proteins that are proteolysed after TBI (myelin basic protein [MBP] and myelin oligodendrocyte specific protein [MOSP]). Unique in vivo cleavage sites in proteolysis-prone protein substrates will be identified with state-of-the- art proteomic techniques. This knowledge will then allow us to generate novel "fragment-specific" antibodies, which will be used to immunohistochemically examine the precise subcellular distribution of these proteolytic products. The same antibody tools will be used to configure enzyme-linked immunoassays (ELISAs) to quantify these axonal and myelin proteolytic products in both brain tissue and cerebrospinal fluid (CSF). The latter method, if successful, will provide a novel and minimally-invasive way of quantifying TBI-associated axonal and myelin damage. These advances in understanding the proteolvtic mechanisms underlying axonal and myelin pathology in TBI will greatly accelerate development of therapies preserving the structural and functional integrity of axons and myelin.


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: 2008 ( Subtotal = $441,401 )
2008	2008	BANYAN BIOMARKERS INC	12085 RESEARCH DRIVE	ALACHUA	FL	32615	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/13/2008	NON-COMPETING CONTINUATION	$441,401
														Subtotal = $441,401

Issue Date FY: 2007 ( Subtotal = $462,530 )
2007	2007	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/17/2007	NON-COMPETING CONTINUATION	$462,530
														Subtotal = $462,530

Issue Date FY: 2006 ( Subtotal = $488,227 )
2006	2006	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/18/2006	NON-COMPETING CONTINUATION	$449,667
2006	2006	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/18/2006	SUPPLEMENT FOR EXPANSION	$38,560
														Subtotal = $488,227

Issue Date FY: 2005 ( Subtotal = $479,318 )
2005	2005	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/28/2005	NEW	$479,318
														Subtotal = $479,318

Grand Total All Awards = $1,871,476

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BIOCHEM. BASIS OF AXONAL & MYELIN INJURY IN HEAD TRAUMA

Award Number: R01NS049175

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: 05/01/2005

PERIOD OF PERFORMANCE END DATE: 04/30/2009

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