U01DC013817

Cell Type Specific Transcriptional Cascades in Inner Ear Development - Disabling Age-Related Hearing Loss (ARHL) afflicts greater than 50% of the population over the age of 70. The progressive loss of sensory hair cells (HCs) of the cochlea, primarily the outer HCs (OHCs), is either the cause or the final common pathology of most forms of ARHL. However, the molecular basis of ARHL is unknown, impeding development of targeted interventions.

Furthermore, attempts to reprogram progenitor cells towards cochlear HC fates result primarily in immature HC-like cells, similar to vestibular HCs. For these reasons, the study of the molecular pathways underlying OHC differentiation and survival is critical.

Transcription factors (TFs) are key regulators of gene expression. When associated with disease, identifying the upstream regulators and downstream targets of a TF is an effective route to determine additional key players in the same process.

In this competitive renewal, we build upon our previous success, identifying critical roles for the RFX and IKZF2 TFs in OHC differentiation, function, and survival, and follow up with two specific aims designed to elucidate their molecular mechanism within the HC/OHC genetic programs:

Group 1 RFX TFs (RFX1/2/3) are master regulators of ciliogenesis. However, while OHCs lacking RFX1/3 die within 12 hours from the onset of hearing, they have normal bundle development. RFX2 is transiently expressed in the developing HCs, possibly preventing a ciliogenesis defect with loss of RFX1/3. We therefore hypothesize that Group 1 RFX TFs have a dual role in HC development, with an early role in hair bundle formation, and later role in terminal differentiation and survival.

Specific Aim 1: To identify the mechanisms by which RFX TFs support embryonic as well as early post-natal cochlear hair cell differentiation.

IKZF2 is a key regulator of OHC gene expression, precisely regulated to express only in OHCs starting from P4. We hypothesize that: (1) Deletion of IKZF2 target genes will reveal genes essential for OHC function and survival; (2) IKZF2 is required for maintenance of mature OHCs; and (3) IKZF2 expression is regulated by a master-regulator of OHC maturation.

Specific Aim 2: To identify the mechanism by which IKZF2 leads to OHC differentiation, to determine its role in mature OHCs, and to identify its upstream regulatory network.

To accomplish these aims, we combine novel protocols for OHC-specific multi-omic analyses with state-of-the-art bioinformatics, and characterization of novel mouse models to validate the roles of candidate genes in hearing.

Successful completion of these aims will: (1) Impact our understanding of OHC differentiation and survival; (2) Functionally characterize the roles of key RFX and IKZF2 target genes in hearing; (3) Result in transcriptomic and epigenetic maps of differentiating and mature OHCs which will be applied to inform studies for HC regeneration/identifying candidate genes for ARHL; and (4) Generate numerous mouse models for RFX and IKZF2 target genes, which will be readily available to the scientific community.

Additionally, all of the data generated as part of this proposal will be shared via the GEAR (UMGEAR.ORG).

University Of Maryland, Baltimore

TO INVESTIGATE SOLUTIONS TO PROBLEMS DIRECTLY RELEVANT TO INDIVIDUALS WITH DEAFNESS OR DISORDERS OF HUMAN COMMUNICATION IN THE AREAS OF HEARING, BALANCE, SMELL, TASTE, VOICE, SPEECH, AND LANGUAGE. THE NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS (NIDCD) SUPPORTS RESEARCH AND RESEARCH TRAINING, INCLUDING INVESTIGATION INTO THE ETIOLOGY, PATHOLOGY, DETECTION, TREATMENT, AND PREVENTION OF DISORDERS OF HEARING AND OTHER COMMUNICATION PROCESSES, PRIMARILY THROUGH THE SUPPORT OF BASIC AND APPLIED RESEARCH IN ANATOMY, AUDIOLOGY, BIOCHEMISTRY, BIOENGINEERING, EPIDEMIOLOGY, GENETICS, IMMUNOLOGY, MICROBIOLOGY, MOLECULAR BIOLOGY, THE NEUROSCIENCES, OTOLARYNGOLOGY, PSYCHOLOGY, PHARMACOLOGY, PHYSIOLOGY, PSYCHOPHYSICS, SPEECH-LANGUAGE PATHOLOGY, AND OTHER SCIENTIFIC DISCIPLINES. THE NIDCD SUPPORTS: (1) RESEARCH INTO THE EVALUATION OF TECHNIQUES AND DEVICES USED IN DIAGNOSIS, TREATMENT, REHABILITATION, AND PREVENTION OF DISORDERS OF HEARING AND OTHER COMMUNICATION PROCESSES, (2) RESEARCH INTO PREVENTION AND EARLY DETECTION AND DIAGNOSIS OF HEARING LOSS AND SPEECH, VOICE, AND LANGUAGE DISORDERS AND RESEARCH INTO PREVENTING THE EFFECTS OF SUCH DISORDERS BY MEANS OF APPROPRIATE REFERRAL AND REHABILITATION, (3) RESEARCH INTO THE DETECTION, TREATMENT, AND PREVENTION OF DISORDERS OF HEARING AND OTHER COMMUNICATION PROCESSES IN THE ELDERLY POPULATION AND ITS REHABILITATION TO ENSURE CONTINUED EFFECTIVE COMMUNICATION SKILLS, AND (4) RESEARCH TO EXPAND KNOWLEDGE OF THE EFFECTS OF ENVIRONMENTAL AGENTS THAT INFLUENCE HEARING OR OTHER COMMUNICATION PROCESSES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENCOURAGE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.173 - Research Related to Deafness and Communication Disorders

National Institute on Deafness and Other Communication Disorders (NIDCD) [HHS - NIH]

Baltimore, Maryland 21201 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 56% from $1,033,462 to $1,615,795.