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Examination of Ornithine Decarboxylase Antizyme RNA Structure and Function from Various Organisms for the Development of Antibiological Agents

Award Number: R15GM151702
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Examination of Ornithine Decarboxylase Antizyme RNA Structure and Function from Various Organisms for the Development of Antibiological Agents - PROJECT SUMMARY Nearly all organisms possess the capability to synthesize the natural polyamines - putrescine, spermidine and spermine - which are essential for cell growth and differentiation. Due to the ability of polyamines to interact with nearly every biomolecule - DNA, RNA, phospholipids, proteins and ATP, to name a few - they play many roles within the cell in order to support cell growth. It has been well documented that polyamine levels in mammalian cells correlate with the rate of cell growth, high polyamine concentrations have been observed in rapidly proliferating cells and low concentrations have been measured in slow-growing or quiescent cells. Not surprisingly, the transport and metabolism of polyamines are highly regulated by complex feedback mechanisms. Ornithine decarboxylase (ODC) is the key regulatory enzyme in polyamine biosynthesis. ODC homeostasis affects cell growth and cancer development. ODC over-expression has been observed in many tumor types, including prostate, breast, and skin cancers. Both ODC and cellular uptake of polyamines is inhibited by Ornithine Decarboxylase Antizyme (OAZ). The making of Antizyme protein from OAZ mRNA requires translational frameshifting at a highly conserved site to bypass premature termination. Mammalian OAZ mRNAs further possess a pseudoknot (PK) RNA 3¢ to the frameshift site that stimulates +1 frameshifting. Moreover, frameshifting is stimulated by polyamines, thus providing a feedback mechanism whereby the accumulation of metabolic products inhibits biosynthesis. Although the role of the OAZ pseudoknot RNA element (further designated OAZ-PK) in polyamine-dependent frameshifting has been investigated, it has not been examined as a distinct polyamine “sensor”. Riboswitches are elements within noncoding regions of mRNAs that directly bind to cellular metabolites and modulate gene expression. Many riboswitches provide a mechanism of feedback regulation for gene products within the biosynthetic pathway of the cognate metabolite. Riboswitches are widespread among bacteria, and one class further resides in fungi and plants, but no riboswitches have been found in animals. It is proposed that the OAZ-PK RNA functions as a riboswitch, and herein evidence is provided that this noncoding RNA is a polyamine sensor. This RNA element is highly conserved among vertebrate genes required for spermine biosynthesis. Development of drugs that target putative spermine riboswitches from different organisms might therefore be used for wide-ranging purposes such as anticancer agents, antifungal agents, or pesticides. This proposal will examine the structure and function of the OAZ-PK RNA from various organisms, including those of biomedical relevance – human, pathogenic fungi and disease harboring insects - with the following specific aims: (1) examine the specificity and affinity of polyamine binding to OAZ RNAs from various organisms, (2) investigate the three-dimensional structure of OAZ RNAs, and (3) explore the role of Antizyme OAZ RNAs from various organisms in control of gene expression.


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 = $0 )
2026	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Biomedical Research and Research Training	000	1	7/29/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $440,999 )
2023	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Biomedical Research and Research Training	000	1	7/26/2023	NEW	$440,999
														Subtotal = $440,999

Grand Total All Awards = $440,999

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Examination of Ornithine Decarboxylase Antizyme RNA Structure and Function from Various Organisms for the Development of Antibiological Agents

Award Number: R15GM151702

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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