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FUNCTIONAL STUDIES OF UBIQUILIN

Award Number: R01GM066287
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2003
PERIOD OF PERFORMANCE END DATE: 02/29/2012

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FUNCTIONAL STUDIES OF UBIQUILIN - DESCRIPTION (provided by investigator): A common theme that is emerging from studies of neurodegenerative disorders is the realization that many of them are associated, or caused, by defects in protein degradation pathways involving either the ubiquitin-proteasome system or autophagy. The ubiquitin-proteasome degradation pathway is the major pathway used in cells in which misfolded, damaged, and unwanted proteins are first tagged with a chain of four or more ubiquitin molecules and is then recognized and degraded by the proteasome. The autophagy pathway is similar in many respects to the ubiquitin-proteasome degradation pathway, except that proteins as well as organelles are targeted to the lysosome instead of the proteasome. At present it is not known how cells select one or both of these pathways to degrade a particular protein. Our laboratory identified ubiquilin, the founding member of a new class of proteins that appears to regulate protein degradation in cells. During the last funding period, we discovered that ubiquilin interacts with a novel endoplasmic reticulum (ER)- and nuclear envelope-localized protein that we named erasin. We found that erasin promotes endoplasmic reticulum- associated protein degradation (ERAD), a regulated pathway in which misfolded proteins in the ER are extracted and degraded in a ubiquitin-dependent manner by the proteasome. We found that erasin levels are increased by ER stress and that both ubiquilin and erasin protein levels are increased in neurons undergoing neurofibrillary degeneration in Alzheimer's disease. In other studies we found that ubiquilin and erasin interact functionally in ERAD and that they colocalize and are required for autophagosome formation during autophagy. The goal of this proposal is to characterize the functional role of ubiquilin and erasin proteins in cells, with particular emphasis of their roles in ERAD and autophagy. We propose three aims. In Aim 1, we will determine the role of ubiquilin-erasin interaction in ERAD. In Aim 2, we will determine the role of ubiquilin-erasin interaction in autophagy. Finally in Aim 3 we will characterize erasin-interacting proteins and determine the structure and mechanism of targeting of the ER-membrane-localization sequence of erasin. Together these studies should lead to a better understanding of the function of ubiquilin and erasin in protein degradation pathways and the role of the proteins in health and pathological processes. Proteins carry out many vital functions in organisms, but to do so, they need to be correctly folded. Unfortunately proteins tend to misfold, either because they contain genetic mutations or because of environmental influences. In fact, accumulation of misfolded proteins is now known to cause many human diseases, particularly neurodegenerative diseases like Alzheimer's disease, Huntingtons's disease, Lou Gehrig's disease, and Parkinson's disease. This proposal is directed towards studies of ubiquilin and erasin, two new proteins that we discovered that are involved in the removal of misfolded proteins in cells. The results obtained from this proposal will not only lead to a better understanding of how misfolded proteins are cleared from cells, but also could lead to new therapies to treat human diseases caused by protein misfolding.


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: 2011 ( Subtotal = $301,381 )
2011	2011	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	9	7/8/2011	NON-COMPETING CONTINUATION	$27,398
2011	2011	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	9	3/31/2011	NON-COMPETING CONTINUATION	$273,983
														Subtotal = $301,381

Issue Date FY: 2010 ( Subtotal = $335,176 )
2010	2010	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	003	8	4/19/2010	NON-COMPETING CONTINUATION	$304,425
2010	2009	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	004	6	6/1/2010	NON-COMPETING CONTINUATION	$1,469
2010	2009	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	6	4/13/2010	NON-COMPETING CONTINUATION	-$154,837
2010	2009	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	005	7	6/1/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1,469
2010	2009	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	6	4/13/2010	NON-COMPETING CONTINUATION	$30,750
2010	2009	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	7	4/15/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$154,838
														Subtotal = $335,176

Issue Date FY: 2009 ( Subtotal = $307,500 )
2009	2009	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	6	2/16/2009	NON-COMPETING CONTINUATION	$276,750
2009	2009	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	6	6/8/2009	NON-COMPETING CONTINUATION	$30,750
														Subtotal = $307,500

Issue Date FY: 2008 ( Subtotal = $307,500 )
2008	2008	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	5	3/24/2008	COMPETING CONTINUATION	$307,500
														Subtotal = $307,500

Issue Date FY: 2007 ( Subtotal = $96,674 )
2007	2007	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	4	9/10/2007	SUPPLEMENT FOR EXPANSION	$96,674
														Subtotal = $96,674

Issue Date FY: 2006 ( Subtotal = $287,120 )
2006	2006	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	4	4/28/2006	NON-COMPETING CONTINUATION	$287,120
														Subtotal = $287,120

Issue Date FY: 2005 ( Subtotal = $294,030 )
2005	2005	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	4/29/2005	NON-COMPETING CONTINUATION	$294,030
														Subtotal = $294,030

Issue Date FY: 2004 ( Subtotal = $294,030 )
2004	2004	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	4/28/2004	NON-COMPETING CONTINUATION	$294,030
														Subtotal = $294,030

Issue Date FY: 2003 ( Subtotal = $294,030 )
2003	2003	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Cell Biology and Biophysics Research	000	1		NEW	$294,030
														Subtotal = $294,030

Grand Total All Awards = $2,517,441

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FUNCTIONAL STUDIES OF UBIQUILIN

Award Number: R01GM066287

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2003

PERIOD OF PERFORMANCE END DATE: 02/29/2012

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