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ROLE OF RYRS AND DHPRS AND CA2+ ENTRY IN BETA-AMYLOID MEDIATED CA2+ DYSREGULATION

Award Number: K01AR053114
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2007
PERIOD OF PERFORMANCE END DATE: 07/31/2010

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ROLE OF RYRS AND DHPRS AND CA2+ ENTRY IN BETA-AMYLOID MEDIATED CA2+ DYSREGULATION - DESCRIPTION (provided by the applicant): The principal investigator of this proposal, Dr. Alexander Shtifman, is an Associate Investigator in Neurology at St. Elizabeth's Medical Center/Tufts University School of Medicine. The work outlined in this proposal will serve to fund the mentored transition of Dr. Shtifman from a research associate to an independent academic investigator at St. Elizabeth's Medical Center/ Tufts Medical School, which will lead to an application for R01 level funding. The mentors in this proposal are Dr. Querfurth, who is an independent clinical scientist with extensive experience in adenoviral gene delivery and in the field of the Inclusion Body Myositis (IBM) and Dr. Lopez, who is an independent scientist with extensive experience in microelectrode recordings. A committee consisting of Dr. Lopez, Dr. Querfurth and Dr. Westerman will be advising Dr. Shtifman and will carefully oversee his progress. The environment in which the proposed work will be carried out at Tufts and Harvard Medical Schools, both of which are world class scientific institutions, where biomedical research is performed at the highest level, with intimate associations between clinical and basic science disciplines. In this proposal Dr. Shtifman will investigate the effects of expression of A¿1-42 (A¿) on Ca2+ dysregulation in skeletal muscle as it relates to IBM. This study will test the hypothesis that the intracellular deposits of A¿ lead to Ca2+ dysregulation by pathologic modulation of active and passive Ca2+ release through RyR1, voltage-mediated Ca2+ influx through the a1sDHPR and store operated Ca2+ entry. The aims of this proposal are:1) Determine the roles of RyRs, DHPRs and SOCs in A¿-mediated, passive elevation in resting [Ca2+]i 2) Determine effects of A¿ on depolarization and ligand-mediated Ca2+ release from RyRs, as well as its effects on store operated Ca2+ entry in myotubes and 3) Determine the effects of amyloids on depolarization and ligand-mediated Ca2+ release from RyRs and on store operated Ca2+ entry in pAPP-over-expressing transgenic mice. The participation of RyRs, DHPRs and SOCs in A¿-mediated passive Ca2+ elevation will be determined by examining resting [Ca2+]i and Vm changes myotubes and muscle fibers with microelectrode recordings. The effects of A¿ on intracellular Ca2+ release and Ca2+ entry will be determined with high-speed fluorescence imaging. To determine effects of A¿ on local Ca2+ release, Ca2+ spark parameters will be compared between control and A¿-expressing cells using laser scanning confocal microscopy. To regulate the level and temporal expression of A¿, Dr. Shtifman will use the lentiviral Tet-Off expression system for permanent expressions of A¿. The results of these findings will provide new insights into the effects of the intracellular deposition of A¿ in IBM and could lead to design of the future therapeutic agents.


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 = $124,871 )
2009	2009	CARITAS ST ELIZABETH`S MEDICAL CENTER OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/23/2009	NON-COMPETING CONTINUATION	$124,871
														Subtotal = $124,871

Issue Date FY: 2008 ( Subtotal = $124,874 )
2008	2008	CARITAS ST ELIZABETH`S MEDICAL CENTER OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	7/18/2008	NON-COMPETING CONTINUATION	$124,874
														Subtotal = $124,874

Issue Date FY: 2007 ( Subtotal = $124,876 )
2007	2007	CARITAS ST ELIZABETH`S MEDICAL CENTER OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/21/2007	NEW	$124,876
														Subtotal = $124,876

Grand Total All Awards = $374,621

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ROLE OF RYRS AND DHPRS AND CA2+ ENTRY IN BETA-AMYLOID MEDIATED CA2+ DYSREGULATION

Award Number: K01AR053114

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2007

PERIOD OF PERFORMANCE END DATE: 07/31/2010

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