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MOLECULAR AND FUNCTIONAL PROPERTIES OF THE TRPM2 CATIOIN CHANNEL

Award Number: R01GM063954
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: 06/01/2002
PERIOD OF PERFORMANCE END DATE: 08/31/2011

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MOLECULAR AND FUNCTIONAL PROPERTIES OF THE TRPM2 CATIOIN CHANNEL - DESCRIPTION (provided by applicant): The transient receptor potential (TRP) ion channel family recently emerged as harboring crucial channel proteins involved in processes such as sensory perception, magnesium homeostasis or apoptosis. We identified TRPM2, a member of the TRP family, as a calcium-permeable cation channel gated by the novel second messenger ADP-ribose (ADPR) through the channel's intrinsic pyrophosphatase domain. TRPM2 is expressed in a variety of cell types, including pancreatic beta cells and neutrophils. Recently, the role of the molecules in the metabolic network surrounding ADPR on the functional properties of TRPM2 have emerged. Here, the novel calcium-release compound cADPR and other adenine dinucleotides materialize as crucial factors in TRPM2 physiology and hence processes involving cellular calcium homeostasis. Based on its primary activation by ADPR and reactive oxygen species, TRPM2 may have a function in cellular stress and remains a prime candidate for being involved in the apoptotic process. To further our understanding of TRPM2 in cell physiology, we propose experiments in Specific Aim 1 that will focus on the function of TRPM2 in events initiated by adenine-nucleotides. We hypothesize that TRPM2 may function as dual calcium influx and calcium release channel by taking advantage of a TRPM2 overexpressing cell system and a TRPM2 knock-out mouse model. We will explore agonist-receptor interactions engaging the main candidate in generating adenine dinucleotides, namely CD38. We will investigate the involvement of TRPM2 in cell death using a streptozotocin-based mouse model for diabetes type-1. These experiments will be performed in an expression system and mouse neutrophils and beta cells isolated from wild-type, CD38, PARP and TRPM2 knock-out mice models using a combination of patch-clamp, imaging and apoptotic studies. In Specific Aim 2 we will investigate the molecular determinants of TRPM2 agonist binding and address the question whether calmodulin is the mediator of the calcium-dependent facilitation of TRPM2. Understanding TRPM2 and adenine-dinucleotide function in calcium signaling will refine our knowledge of calcium regulation in tissues expressing this ion channel and may provide new targets for therapeutic interference in processes involving TRPM2 function, including diabetes-causing cell death of pancreatic beta cells.


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: 2010 ( Subtotal = $309,042 )
2010	2010	QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL STREET	HONOLULU	HI	96813	HONOLULU	USA	Biomedical Research and Research Training	000	8	8/30/2010	NON-COMPETING CONTINUATION	$309,042
														Subtotal = $309,042

Issue Date FY: 2009 ( Subtotal = $312,164 )
2009	2009	QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL STREET	HONOLULU	HI	96813	HONOLULU	USA	Biomedical Research and Research Training	000	7	8/26/2009	NON-COMPETING CONTINUATION	$312,164
2009	2009	QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL STREET	HONOLULU	HI	96813	HONOLULU	USA	Biomedical Research and Research Training	001	7	9/7/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $312,164

Issue Date FY: 2008 ( Subtotal = $312,164 )
2008	2008	QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL STREET	HONOLULU	HI	96813	HONOLULU	USA	Biomedical Research and Research Training	000	6	8/25/2008	NON-COMPETING CONTINUATION	$312,164
														Subtotal = $312,164

Issue Date FY: 2007 ( Subtotal = $322,138 )
2007	2007	QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL STREET	HONOLULU	HI	96813	HONOLULU	USA	Biomedical Research and Research Training	000	5	9/15/2007	COMPETING CONTINUATION	$322,138
														Subtotal = $322,138

Issue Date FY: 2005 ( Subtotal = $285,250 )
2005	2005	QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL STREET	HONOLULU	HI	96813	HONOLULU	USA	Biomedical Research and Research Training	000	4	5/30/2005	NON-COMPETING CONTINUATION	$285,250
														Subtotal = $285,250

Issue Date FY: 2004 ( Subtotal = $285,250 )
2004	2004	QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL STREET	HONOLULU	HI	96813	HONOLULU	USA	Biomedical Research and Research Training	000	3	5/28/2004	NON-COMPETING CONTINUATION	$285,250
														Subtotal = $285,250

Issue Date FY: 2003 ( Subtotal = $285,250 )
2003	2003	QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL STREET	HONOLULU	HI	96813	HONOLULU	USA	Cell Biology and Biophysics Research	000	2	5/26/2003	NON-COMPETING CONTINUATION	$285,250
														Subtotal = $285,250

Issue Date FY: 2002 ( Subtotal = $285,250 )
2002	2002	QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL STREET	HONOLULU	HI	96813	HONOLULU	USA	Cell Biology and Biophysics Research	000	1	4/25/2002	NEW	$285,250
														Subtotal = $285,250

Grand Total All Awards = $2,396,508

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MOLECULAR AND FUNCTIONAL PROPERTIES OF THE TRPM2 CATIOIN CHANNEL

Award Number: R01GM063954

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: 06/01/2002

PERIOD OF PERFORMANCE END DATE: 08/31/2011

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