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ROLE OF NOTCH3 SIGNALING IN HYPERTENSIVE ARTERIOPATHY

Award Number: R01HL071649
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2003
PERIOD OF PERFORMANCE END DATE: 05/31/2007

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ROLE OF NOTCH3 SIGNALING IN HYPERTENSIVE ARTERIOPATHY - DESCRIPTION (provided by applicant): The pathogenesis of hypertension-induced target organ damage is related to long-term changes in vessel function and structure determined by signaling pathways governing cell growth, programmed cell death, inflammation and matrix modulation. Within the spectrum of identified arteriopathies, CADASIL is a heritable syndrome of systemic small vessel disease predisposing to stroke and vascular dementia. The etiological basis for this syndrome is mutations within one of the Notch family of genes, Notch3. We have recently extended this clinical observation by studying hypertensive vessels and documenting the up-regulation of Notch3 expression in association with maladaptive vascular remodeling. Taken together, these clinical and animal model data support our central hypothesis that Notch3 is a major determinant of vascular structure. Although it is well established that the vascular complications of hypertension are associated with pathological hypertrophy and matrix deposition, the molecular basis of this phenomenon remains poorly defined. Our preliminary data provides provocative new links between the pathology of hypertensive arteriopathy, the putative mediator TGF-beta1 and the Notch3 transcriptional pathway. The proposed project will test the central hypothesis that Notch3 signaling is a critical determinant of maladaptive hypertensive vascular remodeling by up-regulating a key downstream molecular mediator of VSMC hypertrophy and matrix production--TGF-beta1-through the activation of an RBP-Jk- and HRT2-dependent transcriptional pathway. The hypothesis will be tested in vitro and in vivo by systematically implementing both a loss- and gain-of- function strategy, while addressing two fundamental questions: 1) What are the downstream determinants of hypertrophy and matrix production modulated by Notch3 in VSMC and 2) What is the biological significance of Notch3 signaling as a functional and structural determinant of maladaptive hypertensive vascular remodeling and target organ damage in vivo? Specifically, we will: Aim 1: Define the essential role of the Notch3-RBP-Jk--HRT2 signaling pathway as a determinant of TGF-beta1 expression in cultured VSMC. Aim 2: Determine the functional role of a gain of Notch3 signaling in promoting maladaptive vascular remodeling and target organ damage in the context of secondary hypertension in Notch3 transgenic mice. Aim 3: Determine the essential mediator role of Notch3 signaling in promoting maladaptive hypertensive vascular remodeling and target organ damage in the context of secondary hypertension in Notch3 null mice. Aim 4: Determine the essential mediator role of Notch3 signaling in promoting maladaptive hypertensive vascular remodeling and target organ damage in the context of genetic hypertension in Notch3 null mice. The successful completion of the aims of this proposal are anticipated to provide novel mechanistic insights into the determinants of maladaptive vascular remodeling that may have important clinical implications for preventing hypertension-induced target organ damage.


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: 2004 ( Subtotal = $307,600 )
2004	2004	ADVANCED CARDIOVASCULAR SYSTEMS INC	3200 LAKESIDE DRIVE	SANTA CLARA	CA	95054	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	6/29/2004	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$307,600
														Subtotal = $307,600

Issue Date FY: 2003 ( Subtotal = $319,500 )
2003	2003	MOREHOUSE SCHOOL OF MEDICINE	720 WESTVIEW DRIVE, S.W.	ATLANTA	GA	30310	FULTON	USA	Cardiovascular Diseases Research	000	1	7/1/2003	NEW	$319,500
														Subtotal = $319,500

Grand Total All Awards = $627,100

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ROLE OF NOTCH3 SIGNALING IN HYPERTENSIVE ARTERIOPATHY

Award Number: R01HL071649

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2003

PERIOD OF PERFORMANCE END DATE: 05/31/2007

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