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The role of IGF-1 signaling in vascular smooth muscle cells in age-related vascular cognitive impairment and dementia

Award Number: R01AG070915
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The role of IGF-1 signaling in vascular smooth muscle cells in age-related vascular cognitive impairment and dementia - PROJECT SUMMARY/ABSTRACT Age-related vascular cognitive impairment and dementia (VCID), a subgroup of Alzheimer’s Disease and Related Dementias (ADRD) is a common cause of disability and reduced quality of life among the elderly. Extensive recent data have demonstrated that microvascular pathologies in the brain play a central role in these processes. One such pathology is cerebral microhemorrhages (CMH) which are the result of rupture of small intracerebral blood vessels and progressively impairs neuronal function. The incidence of CMH dramatically increases with age and hypertension is one of the major causes for age-related cognitive decline. Yet the underlying cellular mechanisms for CMH and increased vascular fragility are unknown, and thus therapeutic interventions to mitigate CMH are not available. Blood vessel integrity requires plasticity of vascular smooth muscle cells (VSMCs), which exhibit an adaptive switch from a highly contractile to a protective, anti-fragility phenotype in response to stress. Aging fundamentally alters VSMC phenotypic switching, suppressing the adoption of these protective VSMC features, which are otherwise promoted by insulin-like growth factor (IGF)-1. Circulating IGF-1 levels are dramatically decreased with age. Low IGF-1 levels increase the risk for cerebromicrovascular disease and promote the development of CMH in our rodent models, supporting a role for IGF-1 deficiency in age-related vascular fragility. Our hypothesis is that impaired VSMC plasticity and function due to IGF-1 deficiency has a fundamental role in increased cerebrovascular fragility and development of CMH and cognitive decline with age. Aim 1 will test the hypothesis that VSMCs contribute to the development of VCID/ADRD phenotypes in IGF-1 signaling-deficient models. We will use novel VSMC-specific IGF- 1 receptor knockout lines to probe the role of VSMCs in the development of CMH, impaired myogenic autoregulation in response to hypertension, and the consequent development of cognitive decline. Aim 2 will determine the dynamic balance between VSMCs with maladaptive phenotypes and VSMCs with protective phenotypes induced by age-dependent decrease of IGF1. In this aim we will address the question of VSMC plasticity in vivo, evaluating both protective and maladaptive VSMC phenotypes in the cerebrovasculature of Igf1r-deficient CMH models. Aim 3 will evaluate the transcriptional mechanisms governing maladaptive and protective VSMC phenotypes in regions of vascular fragility/CMH and in surrounding intact vessels. Lineage tracing genetic mouse models of aging and IGF-1 deficiency, coupled with single-cell RNA-sequencing, will be used to evaluate the role of novel transcriptional regulators in the adoption of diverse VSMC phenotypes. Pro- and anti-fragility VSMC phenotypic states will be spatially overlaid with the location of CMH to test the hypothesis that CMH occur primarily in regions where VSMCs show a maladaptive phenotype. These scientifically and technically innovative studies will significantly enhance our understanding of the role of IGF-1 deficiency in the development of CMH and will provide insight into underlying cellular mechanisms which are critical for the development of effective therapies.


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: 2024 ( Subtotal = $357,100 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	4	6/4/2024	NON-COMPETING CONTINUATION	$357,100
														Subtotal = $357,100

Issue Date FY: 2023 ( Subtotal = $357,100 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	3	5/16/2023	NON-COMPETING CONTINUATION	$357,100
														Subtotal = $357,100

Issue Date FY: 2022 ( Subtotal = $357,100 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	2	5/5/2022	NON-COMPETING CONTINUATION	$357,100
														Subtotal = $357,100

Issue Date FY: 2021 ( Subtotal = $357,100 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	9/16/2021	NEW	$357,100
														Subtotal = $357,100

Grand Total All Awards = $1,428,400

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The role of IGF-1 signaling in vascular smooth muscle cells in age-related vascular cognitive impairment and dementia

Award Number: R01AG070915

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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