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STIMULATION OF SMC GROWTH BY SEROTONIN

Award Number: R01HL032723
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 07/01/1984
PERIOD OF PERFORMANCE END DATE: 08/31/2007

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STIMULATION OF SMC GROWTH BY SEROTONIN - DESCRIPTION (provided by applicant): There is considerable evidence now available that supports an important rote for the serotonin (5-HT) transporter, a member of the NaCl- dependent transporter gene family, in the development of pulmonary vascular remodeling and hypertension. Transcription of this transporter is stimulated by hypoxia and the transporter participates in 5-HT-induced pulmonary artery (PA) smooth muscle cell (SMC) hyperplasia/hypertrophy. Based on our studies done largely during the last funding period, we hypothesize that there are specific intermediate intracellular signaling pathways through which the mitogenic action of 5-HT occurs (denoted in Figure 1). We plan in this proposal to further study these intermediate signals by: 1) examining the PA SMC NAD(P)H oxidase that is stimulated in response to 5-HT transport; 2) characterizing the role of Src-Fak non-receptor kinases in signal transduction, cyclin D1 gene regulation, cell growth and cytoskeletal reorganization produced by 5-HT; 3) evaluating transcription factors (in particular STAT and GATA) that may be linked to 5-HT transporter stimulation of SMC growth; and 4) assessing the role of a concomitant 5-HT4-like receptor action on the same SMC that can convert the growth stimulatory effect to a growth inhibitory one. For these studies we will use bovine PA SMCs, with which we have had considerable experience, but will shift to PA SMCs of the human, rat and mouse species as needed to answer specific questions, or where reagents being used require specific species homology. Methodologies will include, but not be limited to, Western and Northern analyses, electrophoretic mobility shift assays, immunoblotting, PCR technology, lipid-mediated transient transfections, adenoviralmediated gene transfer, and use of reporter gene constructs, all of which are ongoing in our laboratory. We anticipate that a fuller understanding of the intracellular processes responding to 5-HT transporter activation may allow development of new strategies for treating pulmonary hypertension.


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: 2006 ( Subtotal = $355,933 )
2006	2006	NEW ENGLAND MEDICAL CENTER HOSPITALS, INC	750 WASHINGTON STREET	BOSTON	MA	02111	SUFFOLK	USA	Lung Diseases Research	000	22	7/22/2006	NON-COMPETING CONTINUATION	$355,933
														Subtotal = $355,933

Issue Date FY: 2005 ( Subtotal = $364,500 )
2005	2005	NEW ENGLAND MEDICAL CENTER HOSPITALS, INC	750 WASHINGTON STREET	BOSTON	MA	02111	SUFFOLK	USA	Lung Diseases Research	000	21	8/1/2005	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $364,500

Issue Date FY: 2004 ( Subtotal = $364,500 )
2004	2004	NEW ENGLAND MEDICAL CENTER HOSPITALS, INC	750 WASHINGTON STREET	BOSTON	MA	02111	SUFFOLK	USA	Lung Diseases Research	000	20	7/26/2004	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $364,500

Issue Date FY: 2003 ( Subtotal = $364,500 )
2003	2003	NEW ENGLAND MEDICAL CENTER HOSPITALS, INC	750 WASHINGTON STREET	BOSTON	MA	02111	SUFFOLK	USA	Lung Diseases Research	000	19	7/25/2003	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $364,500

Issue Date FY: 2002 ( Subtotal = $391,843 )
2002	2002	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Lung Diseases Research	000	18	6/10/2002	COMPETING CONTINUATION	$391,843
														Subtotal = $391,843

Issue Date FY: 2001 ( Subtotal = $300,404 )
2001	2001	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Lung Diseases Research	000	17	3/12/2001	NON-COMPETING CONTINUATION	$300,404
														Subtotal = $300,404

Issue Date FY: 2000 ( Subtotal = $293,047 )
2000	2000	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Lung Diseases Research	000	16	3/15/2000	NON-COMPETING CONTINUATION	$293,047
														Subtotal = $293,047

Issue Date FY: 1999 ( Subtotal = $286,809 )
1999	1999	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Lung Diseases Research	000	15	2/22/1999	NON-COMPETING CONTINUATION	$286,809
														Subtotal = $286,809

Issue Date FY: 1998 ( Subtotal = $286,513 )
1998	1998	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Lung Diseases Research	000	14	4/7/1998	COMPETING CONTINUATION	$286,513
														Subtotal = $286,513

Grand Total All Awards = $3,008,049

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STIMULATION OF SMC GROWTH BY SEROTONIN

Award Number: R01HL032723

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 07/01/1984

PERIOD OF PERFORMANCE END DATE: 08/31/2007

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