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CONFORMATIONAL ANTIBODIES RECOGNIZING AMYLOID EPITOPES

Award Number: R01NS046356
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: 03/01/2003
PERIOD OF PERFORMANCE END DATE: 02/28/2008

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CONFORMATIONAL ANTIBODIES RECOGNIZING AMYLOID EPITOPES - DESCRIPTION (provided by applicant): A number of neurological and other diseases are associated with the formation of protein aggregates called amyloid fibrils. Although the protein component of amyloid is different for different diseases, the three-dimensional shape of the amyloid seems to be the same in all cases. It has proven exceedingly difficult to get detailed structural information on amyloid, compromising our efforts to understand and devise treatments for Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, and an array of other devastating conditions. We have developed antibody molecules that have the unique ability to bind to amyloid fibrils, regardless of the amino acid sequence of the constituent protein. Here we propose to develop these conformational antibodies as tools to improve our understanding of the amyloid structure and how it develops in human diseases. The specific aims are to (1) develop additional antibodies and antibody fragments, (2) structurally characterize these antibodies as a novel window onto the structure of amyloid fibrils, (3) characterize the fundamental basis of the antibody-amyloid interaction, and (4) develop the antibodies into tests for detecting amyloid in tissue and serum, as well as to monitor the emergence of the amyloid motif during in vitro amyloidogenesis. The tools involved in this work will include hybridoma and phage display technology, recombinant expression, mutagenesis, protein modeling and crystallography, immunochemical binding assays, and in vitro amyloid fibril assembly reactions. Since recently described vaccine approaches to amyloid diseases such as AD depend on the generation of antibodies, characterizing the structural basis of the anti-amyloid reaction is important. It is also important to understand the structure of amyloid and how these fibrils grow, as a means toward developing agents that will compromise fibril cytotoxicity and fibril growth. Finally, as a ubiquitous alternative folding pattern of protein polymers, amyloid and its structure is of fundamental importance to our understanding of the molecular basis of life.


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	2006	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	12/9/2008	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1,691
2009	2006	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/9/2008	NON-COMPETING CONTINUATION	$1,691
														Subtotal = $0

Issue Date FY: 2007 ( Subtotal = $324,420 )
2007	2007	UNIVERSITY OF PITTSBURGH	3017 CATHEDRAL OF LEARNING	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/17/2007	NON-COMPETING CONTINUATION	$324,420
														Subtotal = $324,420

Issue Date FY: 2006 ( Subtotal = $312,402 )
2006	2006	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/28/2006	NON-COMPETING CONTINUATION	$312,402
														Subtotal = $312,402

Issue Date FY: 2005 ( Subtotal = $319,920 )
2005	2005	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/25/2005	NON-COMPETING CONTINUATION	$319,920
														Subtotal = $319,920

Issue Date FY: 2004 ( Subtotal = $319,920 )
2004	2004	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/14/2004	NON-COMPETING CONTINUATION	$319,920
														Subtotal = $319,920

Issue Date FY: 2003 ( Subtotal = $346,750 )
2003	2003	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1		NEW	$346,750
														Subtotal = $346,750

Grand Total All Awards = $1,623,412

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CONFORMATIONAL ANTIBODIES RECOGNIZING AMYLOID EPITOPES

Award Number: R01NS046356

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: 03/01/2003

PERIOD OF PERFORMANCE END DATE: 02/28/2008

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