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MURINE MODELS OF HYPOTHYROIDISM AND CONGENITAL DEAFNESS

Award Number: R01DC004566
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/24/2001
PERIOD OF PERFORMANCE END DATE: 08/31/2006

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MURINE MODELS OF HYPOTHYROIDISM AND CONGENITAL DEAFNESS - DESCRIPTION (provided by applicant): The overall, long-term goal of the research proposed in this application is to determine the anatomical and physiological basis of peripheral auditory anomalies associated with congenital hypothyroidism and to initiate an investigation into the molecular nature of associated deficits. In doing so, we hope to expand our understanding of thyroid hormone's role in the normal development of the inner ear and extend our understanding of the auditory consequences of hypothyroidism by considering the relative contribution that discrete inner ear tissues and structures make in the pathogenesis of the disease. The Tshrhyt mutant mouse is ideally suited to meet the needs of the proposed research and will serve as the primary model of hypothyroidism in the proposed study. We also propose to study normal BALB/c mice rendered hypothyroid through the actions of the anti-thyroid drugs, propylthiouracil (PTU) and methimazole (MMI), in an effort to establish a model of hypothyroidism-induced otopathology that will allow us to clarify differences reported in the literature regarding the effects of thyroid hormone deficiency on the auditory periphery, as well as the capacity of thyroid hormone to restore function in diseased animals. The chief hypothesis being tested in this proposal is that abnormal cochlear amplification represents an enduring defect of hypothyroidism-induced otopathology and that normal passive transduction is acquired developmentally over a protracted time course. In that context, in addition to experiments designed to address the primary question directly using in vivo recordings (ABR, CM and DPOAE), as well as in vitro recordings from outer hair cells, we plan to study the morphological and the functional properties of the tectorial membrane, along with its chemical composition, to determine its role in the pathogenesis of the disease. The role of other passive aspects of transduction (e.g., endocochlear potential) will be assessed directly. We also plan to take the first step in a study aimed at determining the molecular and genetic basis of hypothyroidism, using RT-PCR and in situ hybridization to study the expression of transcripts that may affect the expression of cochlear amplification. Finally, we propose to explore the intriguing possibility that the efferent OC system may influence the development of peripheral auditory function. If the main hypotheses proposed here are affirmed, the existing model of auditory system pathology induced by hypothyroidism will be fundamentally revised.


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: 2005 ( Subtotal = $327,600 )
2005	2005	FATHER FLANAGAN'S BOYS' HOME	14100 CRAWFORD STREET	BOYS TOWN	NE	68010	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	5	7/11/2005	NON-COMPETING CONTINUATION	$327,600
														Subtotal = $327,600

Issue Date FY: 2004 ( Subtotal = $327,600 )
2004	2004	FATHER FLANAGAN'S BOYS' HOME	14100 CRAWFORD STREET	BOYS TOWN	NE	68010	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	4	8/5/2004	NON-COMPETING CONTINUATION	$327,600
														Subtotal = $327,600

Issue Date FY: 2003 ( Subtotal = $377,600 )
2003	2003	FATHER FLANAGAN'S BOYS' HOME	14100 CRAWFORD STREET	BOYS TOWN	NE	68010	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	3	8/15/2003	NON-COMPETING CONTINUATION	$327,600
2003	2003	FATHER FLANAGAN'S BOYS' HOME	14100 CRAWFORD STREET	BOYS TOWN	NE	68010	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	001	3	8/15/2003	SUPPLEMENT FOR EXPANSION	$50,000
														Subtotal = $377,600

Issue Date FY: 2002 ( Subtotal = $327,600 )
2002	2002	FATHER FLANAGAN'S BOYS' HOME	14100 CRAWFORD STREET	BOYS TOWN	NE	68010	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	2	8/30/2002	NON-COMPETING CONTINUATION	$327,600
														Subtotal = $327,600

Issue Date FY: 2001 ( Subtotal = $323,596 )
2001	2001	FATHER FLANAGAN'S BOYS' HOME	14100 CRAWFORD STREET	BOYS TOWN	NE	68010	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	1	9/24/2001	NEW	$323,596
														Subtotal = $323,596

Grand Total All Awards = $1,683,996

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MURINE MODELS OF HYPOTHYROIDISM AND CONGENITAL DEAFNESS

Award Number: R01DC004566

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/24/2001

PERIOD OF PERFORMANCE END DATE: 08/31/2006

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