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Expanding the Druggable Human Genome

Award Number: F31CA257090
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 10/01/2024

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Expanding the Druggable Human Genome - PROJECT SUMMARY: Most small molecule drugs elicit their effects by modulating protein function, despite the fact that only a small portion of the genome is translated (~1-2%). Further, only ~15% of the human proteome is considered to be druggable, severely limiting therapeutic pipelines. The scientific challenge is to develop generalizable methods to drug the other ~85% of coding genes. The purpose of this proposal is to advance a radically new paradigm to expand the druggability of the (protein coding) genome by targeting disease-causing genes at the level of their RNA. To do so, we will computationally and biochemically determine RNA secondary structures in the transcriptome, with a focus on disease associated genes, to aid in the design of drug-like small molecules to treat diseases at the RNA level. This innovative approach for targeting the transcriptome could massively expand our ability to treat a wide array of diseases, spanning from genetic disorders to cancer and pathogenic infections, and expanding the repertoire of drug action. The proposed studies synergize the expertise of two laboratories. Dr. Walter Moss’ Lab (sponsor) has developed and implemented robust approaches to precisely define conserved and functional RNA structures throughout the human genome. Dr. Matthew Disney’s lab (co-sponsor) has established a comprehensive program for the design of small molecules that selectively target RNA and modulate disease biology, including those that selectively recruit endogenous nucleases to a desired transcript. Collectively, our synergistic areas of expertise will allow us to define the druggable human genome, drug undruggable protein targets at the level of their mRNAs, and push forward a bench-to-bedside, precision medicine paradigm. In Aim 1, we will define conserved RNA structures throughout the genome, with a focus on validating and targeting conserved structures in mRNAs that encode proteins that are considered undruggable. These studies will define evolutionary conservation across vertebrate genomes to provide key insights into both biology and druggability. We will evaluate and improve model structures using in cellulis RNA structure probing to test predictions and, where needed, provide constraints that can be used to create experimentally informed revised models. In Aim 2 we will generate a list of high value motifs with the highest probability of being druggable, perform functional analyses to determine their effects on gene expression, and deduce interactions.


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 = -$22,159 )
2025	2024	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Cancer Research Manpower	000	4	1/20/2025	NON-COMPETING CONTINUATION	-$22,159
														Subtotal = -$22,159

Issue Date FY: 2024 ( Subtotal = $42,031 )
2024	2024	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Cancer Research Manpower	000	4	5/22/2024	NON-COMPETING CONTINUATION	$42,031
														Subtotal = $42,031

Issue Date FY: 2023 ( Subtotal = $40,751 )
2023	2023	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Cancer Research Manpower	000	3	3/29/2023	NON-COMPETING CONTINUATION	$40,751
														Subtotal = $40,751

Issue Date FY: 2022 ( Subtotal = $39,809 )
2022	2022	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Cancer Research Manpower	000	2	6/24/2022	NON-COMPETING CONTINUATION	$39,809
														Subtotal = $39,809

Issue Date FY: 2021 ( Subtotal = $39,093 )
2021	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Cancer Research Manpower	002	1	2/2/2021	NEW	$0
2021	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Cancer Research Manpower	000	1	12/23/2020	NEW	$38,577
2021	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Cancer Research Manpower	001	1	2/2/2021	NEW	$516
														Subtotal = $39,093

Grand Total All Awards = $139,525

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Expanding the Druggable Human Genome

Award Number: F31CA257090

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 10/01/2024

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