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MicroRNA 34/449 family plays a critical role in choroid plexus differentiation and tumorigenesis

Award Number: R15CA287297
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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MicroRNA 34/449 family plays a critical role in choroid plexus differentiation and tumorigenesis - PROJECT SUMMARY/ABSTRACT Tumors of the choroid plexus (CP) are rare primary brain neoplasms mostly found in children, accounting for up to 20% of brain tumors that occur in the first year of life. CP papilloma (CPP) is typically benign and can be resolved through surgery, but CP carcinoma (CPC) is a particularly aggressive brain cancer. CPC most commonly arises in young children when they are unsuitable for radiation. Despite treatments that include surgery, chemotherapy, and radiation, CPC usually responds poorly. CPC is prone to recurrence and metastasis, with less than 50% of children still alive five years after diagnosis. In addition, survivors often suffer from debilitating long-term treatment effects, including intellectual disability and increased cancer risk. The development of safer and more effective therapies for CPC requires a better understanding of its biology. In this application, accurate experimental models will be used to gain crucial insights into CP differentiation and tumorigenesis, and facilitate the development of novel therapeutic strategies. Human CPCs frequently exhibit mutation of TP53 tumor suppressor and abnormal NOTCH pathway activities. In mice, sustained NOTCH1 expression, or combined inactivation of Rb1 and Trp53 tumor suppressors led to aggressive CP tumor with characteristics of CPC in humans. Multiciliated cells (MCCs) are present in the CP in humans and mice. MCCs in the CP epithelium arise during embryogenesis and are mostly immotile. In contrast, CPCs in humans exhibit solitary cilia, and disturbances to multiciliation program directed by GMNC, a transcriptional regulator of MCC fate in diverse tissues including the CP. Accordingly, NOTCH-driven and Rb1/Trp53-deficient CPC display singular cilia consequent to defects in multiciliation program, suggesting tumor suppression by GMNC multiciliation program. Therefore, the impairment of the multiciliation program enables tumor cell proliferation. Knowledge of GMNC program regulation may facilitate the promotion of multiciliation as a potential therapeutic strategy in CPC. The project will focus on the interactions between the MCC differentiation program and microRNA (miRNA) during CP development and tumorigenesis. Aim 1 will examine whether gene regulation by miRNAs influences multiciliation in the CP. Both in vivo and in vitro studies will be conducted to investigate their role and underlying mechanisms in MCC differentiation in the CP. A novel organoid model will be utilized to characterize miRNA expression during multiciliation in the CP in humans. Transcriptomics studies will be conducted to identify differentially expressed genes and potential miRNA targets in the CP. Though most CPC in humans carry mutations in TP53 tumor suppressor that are associated with increased genomic instability and poor prognosis, molecular mechanisms of TP53-deficient CPC remain poorly understood. Aim 2 will investigate whether gene regulation by miRNAs influences multiciliation in TP53-deficient CPC. Both gain- and loss-of- function studies will be conducted to investigate their role in CPC development. These studies will uncover post- transcriptional mechanisms of CP differentiation and tumorigenesis.


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 = $459,000 )
2025	2025	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Cancer Biology Research	000	1	6/27/2025	NEW	$459,000
														Subtotal = $459,000

Grand Total All Awards = $459,000

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MicroRNA 34/449 family plays a critical role in choroid plexus differentiation and tumorigenesis

Award Number: R15CA287297

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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