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Regulation of choroid plexus epithelial function by klotho

Award Number: R15AG073947
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Regulation of choroid plexus epithelial function by klotho - PROJECT SUMMARY Age-related changes to protein and thus cellular function occur across the brain. Increased understanding of when age-related events become pathological is required both to support healthy brain aging and to develop early and efficacious neurodegenerative disease therapeutics. Among the cells of the brain to experience age- related impairment to structure and function, the choroid plexus epithelial cells stand out as a tissue with untapped potential to support the entire brain parenchyma. Choroid plexus epithelial cells express high levels of Klotho protein. Increasing expression of Klotho enhances but decreasing expression impairs neuronal memory function across species and in models of neurodegenerative disease. Recent work determined that a common human polymorphic variant of Klotho that increases protein is protective against Alzheimer’s disease development and pathology. While Klotho action in and upon cells of the brain parenchyma indicates its effects are brain-wide, little is known about the primary source of brain Klotho, the choroid plexus epithelial cells. Our pilot data indicate that cell-type specific klotho-deficiency impacts longevity, memory, and choroid plexus cell structure and function. These data suggest that Klotho may effects cells throughout the brain because it is critical to choroid plexus epithelial cell activities. Choroid plexus epithelial cells provide physical, nutrient, and signal transduction support to the entire brain. They also function as a physical protective barrier and communication center between body and brain. The long-term goal of the proposed research is to understand the health-related functional consequences of age-related klotho-deficiency from choroid plexus epithelial cells. We will use mouse models to interrogate the central hypothesis that Klotho-deficiency impairs brain parenchyma by disrupting the function of the choroid plexus epithelial cells. In specific aim one, we will use mouse models to determine the role of choroid plexus-specific Klotho expression on memory across lifespan. Using animal models and cellular and molecular techniques, aim two will determine whether choroid plexus epithelial cell structure or function are altered by Klotho-deficiency. The significance of the proposal lies in contributions to understanding the basic biology of Klotho as a protein critical for the normal choroid plexus epithelial cell functions required to sustain and support healthy brain parenchyma across lifespan. We are uniquely situated to expose undergraduate students interested in research and medically focused careers discovery neuroscience research using animal models. The proposal is innovative in its use of novel animal models to allow targeted manipulation of Klotho expression and, in studying the choroid plexus epithelia, studies a tissue-type with unrealized potential to support brain health across lifespan.


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: 2025 ( Subtotal = $0 )
2025	2021	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Aging Research	000	1	8/14/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Aging Research	000	1	7/31/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $436,500 )
2021	2021	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Aging Research	000	1	8/11/2021	NEW	$436,500
														Subtotal = $436,500

Grand Total All Awards = $436,500

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Regulation of choroid plexus epithelial function by klotho

Award Number: R15AG073947

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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