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Heart and vascular responses across the lifespan in Ts65Dn mice, a model of Down syndrome

Award Number: R21HD099573
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Down Syndrome (Ds) is the most common chromosomal cause of intellectual disability that results from triplication of chromosome 21 genes. Persons with Ds demonstrate cognitive deficits in addition to co- morbidities including cardiovascular alterations and pulmonary hypertension. Lower blood pressure at rest and in response to exercise and other stressors are prevalent in Ds. The attenuated cardiovascular reactions to activities of daily living in Ds are autonomically mediated, but likely include other factors such as endothelial dysfunction. These cardiovascular findings are complicated by the fact that Ds is protected from atherosclerosis. Therefore, the mechanisms responsible for cardiovascular alterations in Ds are multifaceted in this population. At this time there is not an appropriately developed cardiovascular model to investigate these important clinical concerns, although a trisomic animal model does exist. Our robust preliminary data reveal attenuated mean arterial blood pressure, diastolic blood pressure and systolic blood pressure in restrained Ts65Dn mice, a model of Ds. Freely moving Ts65Dn mice have lower heart rate than wild-type (WT). Taken together, these data suggest the altered cardiovascular patterns observed in Ts65Dn mice may be representative of people with Ds. This exploratory grant application aims to verify, via a series of physiological experiments, that the Ts65Dn mouse is an appropriate model to study heart and blood pressure differences in Ds. The experiments described in this proposal will further examine cardiovascular alterations in Ts65Dn mice through conscious and reduced preparations, including autonomic nervous system contributions and endothelial dysregulation as a potential mechanism of attenuated vascular tone and cardiac output. Specific Aim 1 will compare the cardiovascular profile and vascular physiology of WT and Ts65Dn mice at 3, 6 and 12 months of age. Blood pressure and heart rate will be quantified across the circadian cycle via radiotelemetry, and we will further distinguish possible mechanistic differences in autonomic control of blood pressure with pharmacological blockade of the sympathetic and parasympathetic nervous system in conscious mice. Arterial stiffness will be quantified in anesthetized mice using pulse wave velocity, and heart rate variability will be used to monitor autonomic tone in both conscious and anesthetized experiments. Arterial isometric tension using an in vitro setup will compare endothelial dependent and independent vasodilation of aorta and mesenteric artery. Specific Aim 2 will quantify baroreflex sensitivity and cardiac function with in vivo pressure-volume loops in WT and Ts65Dn mice. All aims will study male and female mice at 3 months, 6 months and 12 months of age to further describe aging and sex as biological variables in this model. Since individuals with Ds demonstrate characteristics of accelerated aging it will be important to know how heart function and blood pressure responses change with advancing age in WT vs. Ts65Dn. Overall, this project will provide insight into cardiovascular regulation in Ds with the objective of improving the quality of life of persons with this condition. !


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: 2023 ( Subtotal = $0 )
2023	2021	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Aging Research	003	1	9/14/2023	SUPPLEMENT FOR EXPANSION	-$214,857
2023	2021	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	004	1	9/14/2023	SUPPLEMENT FOR EXPANSION	-$112,500
2023	2020	UNIVERSITY OF HEALTH SCIENCES AND PHARMACY IN ST. LOUIS	1 PHARMACY PL	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Child Health and Human Development Extramural Research	005	2	9/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$327,357
2023	2020	UNIVERSITY OF HEALTH SCIENCES AND PHARMACY IN ST. LOUIS	1 PHARMACY PL	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Child Health and Human Development Extramural Research	002	2	9/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2020	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	000	1	5/25/2023	NEW	-$153,010
2023	2020	UNIVERSITY OF HEALTH SCIENCES AND PHARMACY IN ST. LOUIS	1 PHARMACY PL	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Child Health and Human Development Extramural Research	001	2	5/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$153,010
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $350,712 )
2021	2021	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Aging Research	001	1	5/19/2021	SUPPLEMENT FOR EXPANSION	$238,212
2021	2021	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	002	1	8/26/2021	SUPPLEMENT FOR EXPANSION	$112,500
2021	2020	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	000	1	4/6/2021	NEW	$0
														Subtotal = $350,712

Issue Date FY: 2020 ( Subtotal = $426,640 )
2020	2020	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	001	1	8/19/2020	NEW	$0
2020	2020	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	000	1	8/3/2020	NEW	$426,640
														Subtotal = $426,640

Grand Total All Awards = $777,352

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Heart and vascular responses across the lifespan in Ts65Dn mice, a model of Down syndrome

Award Number: R21HD099573

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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