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A Chemosensory-Mechanotransduction System Regulating Ventricular Size and Brain Function

Award Number: R01NS106985
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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A Chemosensory-Mechanotransduction System Regulating Ventricular Size and Brain Function - How the brain determines cerebral ventricular volume, and how that in turn affects brain function, are poorly understood. In patients who develop idiopathic normal pressure hydrocephalus (iNPH) or low pressure hydrocephalus after intracranial hemorrhage, infection or other brain insults, ventricular volume increases in the absence of obstruction to cerebrospinal fluid (CSF) flow, sustained intracranial pressure (ICP) elevations or brain atrophy. iNPH patients display motor apraxia, dementia and incontinence that are often improved by CSF drainage, but the underlying mechanisms are not known. Numerous studies suggest that ependymal motile cilia dysfunction somehow leads to hydrocephalus, albeit via unclear mechanisms. Indeed, some investigators have challenged this notion, suggesting instead that increased CSF production, decreased CSF absorption, or abnormal brain development are responsible. Here we present evidence for an ependymal chemosensory- mechanotransduction system that uses motile cilia to convert chemical signals to changes in flow that govern ependymal cell junction assembly, ventricular wall stiffness and ependymal permeability. By controlling ventricular compliance and the exchange of CSF between the ventricular and interstitial spaces, this system regulates ventricular volume, the relative distribution and composition of fluid in the ventricular and interstitial compartments, and neuronal activity, all without altering ICP. To elucidate why ventriculomegaly and neurological deficits develop in iNPH, we sequenced DNA from iNPH patients to identify iNPH-associated mutations. Most of the iNPH-associated mutations involved genes that encode proteins associated with cilia, and all of the genes showed increased expression in ependymal or choroid plexus cells. iNPH-associated mutations affecting CWH43 or AK9 occurred in 25% of iNPH patients. Mice harboring iNPH-associated CWH43 or AK9 mutations displayed decreased motile cilia number or motility, respectively, and developed ventriculomegaly and gait imbalance characteristic of iNPH. We now show that the ventriculomegaly is accompanied by normal ICP, increased ventricular compliance and permeability, and disassembly of ependymal cell junctions. We and others have discovered multiple receptors that localize to ependymal motile cilia and regulate CSF flow by modulating cilia beat frequency. Mutation of these receptors increases ventricular volume. In normal mice, we find that flow is required to maintain ependymal cell junctions. This process involves activation of ependymal Piezo1, TRPV4, and PKD2 mechanotransduction channels. Induced conditional deletion of Piezo1 or PKD2 in adult mice increases ventricular size. We observed a diurnal increase in ependymal permeability that increases exchange between ventricular CSF and interstitial fluid during sleep. We find that ventriculomegaly in CWH43 or AK9 mutant mice is associated with a task-dependent decrease in neuronal activation in the hippocampus and parietal cortex that may underlie the dementia and motor apraxia of iNPH. We will examine how this ependymal chemosensory-mechanotransduction system regulates ventricular size and brain function.


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: 2026 ( Subtotal = $555,440 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	3/24/2026	NON-COMPETING CONTINUATION	$555,440
														Subtotal = $555,440

Issue Date FY: 2025 ( Subtotal = $588,977 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	8/28/2025	SUPPLEMENT FOR EXPANSION	$33,537
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	4/9/2025	NON-COMPETING CONTINUATION	$555,440
														Subtotal = $588,977

Issue Date FY: 2024 ( Subtotal = $656,051 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/29/2024	COMPETING CONTINUATION	$555,440
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	7/22/2024	SUPPLEMENT FOR EXPANSION	$100,611
2024	2021	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $656,051

Issue Date FY: 2021 ( Subtotal = $670,561 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/20/2021	SUPPLEMENT FOR EXPANSION	$31,969
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/18/2021	NON-COMPETING CONTINUATION	$638,592
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	9/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $670,561

Issue Date FY: 2020 ( Subtotal = $561,865 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/2/2020	NON-COMPETING CONTINUATION	$561,865
														Subtotal = $561,865

Issue Date FY: 2019 ( Subtotal = $561,865 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	9/5/2019	NON-COMPETING CONTINUATION	$561,865
														Subtotal = $561,865

Issue Date FY: 2018 ( Subtotal = $561,865 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/5/2018	NEW	$561,865
														Subtotal = $561,865

Grand Total All Awards = $4,156,624

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A Chemosensory-Mechanotransduction System Regulating Ventricular Size and Brain Function

Award Number: R01NS106985

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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