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GENETIC DISSECTION OF PHOTOTRANSDUCTION

Award Number: R01EY003529
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/1981
PERIOD OF PERFORMANCE END DATE: 08/31/2012

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GENETIC DISSECTION OF PHOTOTRANSDUCTION - DESCRIPTION (provided by applicant): The long-term scientific goal of the research project is to understand the molecular mechanism underlying Drosophila phototransduction. Drosophila photoreceptor cells are photosensitive neurons with a phototransduction cascade similar to that of the Retinal Ganglion Cells (RGC), which contain the photopigment melanopsin, thus being a "Rosetta Stone" for RGC and other photosensitive neurons. Both Drosophila and presumably the light sensitive RGC are characterized by bi-stable rhodopsin that initiates phototranduction with Transient Receptor Potential (TRP) channels as the final target. The specific aims are: i) to elucidate the mechanisms that make the photoreceptor rhabdomere a signaling compartment as a strategy to optimize function. The unknown functional properties of the Ca2+ binding protein, calphotin, will be studied. To this end calphotin levels will be modulated in vivo by overexpression or by RNAi and the physiological consequences will be studied. Moreover, we will examine the putative role of calphotin as a dynamic barrier controlling the free diffusion of Ca2+ between the rhabdomere and the cell body. ii) To study the unknown mechanism underlying light dependent translocation of the TRP-like (TRPL) channel. We will use TRP-TRPL chimeras expressed in the living fly eye to study the effects of various domains of the immobile TRP on translocation of TRPL. Since TRP but not TRPL binds to the INAD scaffold protein, the chimeras will allow elucidating new roles for INAD in phototransduction and whether or not TRP and TRPL form heteromultimeres. iii) To elucidate the unknown mechanism of TRP and TRPL activation by light. Potentially, a phospholipase C (PLC) - mediated phototransduction can activate the channels by at least three putative mechanisms: by second messengers, by removal of inhibition and by change in membrane curvature. More specifically: (a) Activation by the second messengers Inositol 1,4,5 trisphosphate (InsP3), Diacylglycerol (DAG) and subsequently Polyunsaturated Fatty Acids (PUFA) due to hydrolysis of DAG. (b) Activation by a decrease in the concentration of PIP2, thereby removing its inhibitory effect on the channels. (c) Activation by conversion of PIP2 to DAG or PUFA causing membrane lipid packing modifications that changes the curvature of the plasma membrane and thereby activate the channels in a manner similar to activation of mechanosensitive channels. We will examine these possibilities in expression system of Drosophila cell-line which express TRPL and in the native photoreceptor cells by inducing PIP2 hydrolysis without activation of PLC under conditions that change, or do not change membrane curvature. The activation mechanism of the putative mechanosensitive and Ca2+ permeable TRP channel will be used to acquire insights on the involvement of pathological activation of mammalian TRP channels in retinal degeneration and glaucoma. PUBLIC HEALTH RELEVANCE: A powerful approach to identify potentially important proteins for mammalian retinal cells is to look for homologue proteins that have been identified in Drosophila by genetic screens, leading to isolation of mutants defective in retinal processes. Retinal degeneration or glaucoma, which leads by unknown ways to photoreceptor degeneration and apoptosis of retinal ganglion cells (RGC) respectively, may Involve Ca2+ permeable TRP channels activated by mechanical stretch and hypoxia like the Drosophila channels. Therefore, studies on Drosophila TRP and TRPL channels are likely to be relevant for understanding retinal degeneration and mechanisms underlying the damage to RGC by glaucoma.


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 = $160,722 )
2011	2011	HEBREW UNIVERSITY	AUTHORITY FOR RESEARCH DEVELOPMENT	JERUSALEM				ISR	Vision Research	000	31	8/17/2011	NON-COMPETING CONTINUATION	$160,722
														Subtotal = $160,722

Issue Date FY: 2010 ( Subtotal = $163,024 )
2010	2010	HEBREW UNIVERSITY	AUTHORITY FOR RESEARCH DEVELOPMENT	JERUSALEM				ISR	Vision Research	000	30	8/11/2010	NON-COMPETING CONTINUATION	$163,024
														Subtotal = $163,024

Issue Date FY: 2009 ( Subtotal = $162,000 )
2009	2009	HEBREW UNIVERSITY	AUTHORITY FOR RESEARCH DEVELOPMENT	JERUSALEM				ISR	Vision Research	000	29	6/10/2009	COMPETING CONTINUATION	$162,000
														Subtotal = $162,000

Issue Date FY: 2008 ( Subtotal = $154,162 )
2008	2008	HEBREW UNIVERSITY	**	JERUSALEM		00000		ISR	Vision Research	000	28	8/14/2008	NON-COMPETING CONTINUATION	$154,162
														Subtotal = $154,162

Issue Date FY: 2007 ( Subtotal = $157,308 )
2007	2007	HEBREW UNIVERSITY	**	JERUSALEM		00000		ISR	Vision Research	000	27	8/10/2007	NON-COMPETING CONTINUATION	$157,308
														Subtotal = $157,308

Issue Date FY: 2006 ( Subtotal = $158,193 )
2006	2006	HEBREW UNIVERSITY	**	JERUSALEM		00000		ISR	Vision Research	000	26	8/2/2006	NON-COMPETING CONTINUATION	$158,193
														Subtotal = $158,193

Issue Date FY: 2005 ( Subtotal = $162,000 )
2005	2005	HEBREW UNIVERSITY	**	JERUSALEM		00000		ISR	Vision Research	000	25	8/29/2005	COMPETING CONTINUATION	$162,000
														Subtotal = $162,000

Issue Date FY: 2004 ( Subtotal = $162,000 )
2004	2004	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Vision Research	000	24	8/13/2004	NON-COMPETING CONTINUATION	$162,000
														Subtotal = $162,000

Issue Date FY: 2003 ( Subtotal = $162,000 )
2003	2003	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Vision Research	000	23	9/1/2003	NON-COMPETING CONTINUATION	$162,000
														Subtotal = $162,000

Issue Date FY: 2002 ( Subtotal = $162,000 )
2002	2002	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Vision Research	000	22	9/2/2002	COMPETING CONTINUATION	$162,000
														Subtotal = $162,000

Issue Date FY: 2001 ( Subtotal = $114,470 )
2001	2001	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Vision Research	000	21	7/5/2001	NON-COMPETING CONTINUATION	$114,470
														Subtotal = $114,470

Issue Date FY: 2000 ( Subtotal = $111,137 )
2000	2000	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		76100		ISR	Vision Research	000	20	8/3/2000	NON-COMPETING CONTINUATION	$111,137
														Subtotal = $111,137

Issue Date FY: 1999 ( Subtotal = $119,261 )
1999	1999	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		76100		ISR	Vision Research	000	19	8/16/1999	COMPETING CONTINUATION	$119,261
														Subtotal = $119,261

Issue Date FY: 1998 ( Subtotal = $82,509 )
1998	1998	WEIZMANN INSTITUTE OF SCIENCE	NIH (98)					USA	Vision Research	000	18	7/29/1998	NON-COMPETING CONTINUATION	$82,509
														Subtotal = $82,509

Grand Total All Awards = $2,030,786

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GENETIC DISSECTION OF PHOTOTRANSDUCTION

Award Number: R01EY003529

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/1981

PERIOD OF PERFORMANCE END DATE: 08/31/2012

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