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Engineered Nanopores for Single-Molecule Stochastic Sensing

Award Number: R01GM088403
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: 09/28/2009
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Engineered Nanopores for Single-Molecule Stochastic Sensing - Project summary Detailed knowledge of the human genome has opened up a new frontier for the identification of many functional proteins involved in brief physical associations with other proteins. Major perturbations in the strength of these protein-protein interactions (PPI) lead to disease conditions. However, the transient nature of these interactions is difficult to assess quantitatively in heterogeneous solutions using existing methods. These proposed studies are aimed at addressing this challenge by creating selective pore-based sensors that detect these reversible PPI at single-binding event resolution. Precise membrane protein design has been used to produce a large-conductance b-barrel transmembrane pore that tolerates the fusion of a water-soluble protein receptor without deterioration of its overall structure. When a protein ligand present in solution binds to the receptor, transient capture and release events of the ligand can be readily recorded as current transitions between two open substates of the sensor. These manipulations outside the pore lumen have not been conducted previously on other transmembrane proteins. A number of such pore-based sensors will be engineered as a single-polypeptide chain protein to examine PPI in normal and oncogenic conditions. In this project, these receptor-containing sensors will be challenged by inspecting transient PPI of the human Ras GTPase with various interacting partners, such as effectors and other regulatory proteins. The primary motivation for this choice is the pivotal role of this small GTPase in cell signaling and cancer development. The expected immediate outcomes of these proposed studies will be the following: (i) the multiplexed detection of reversible PPI using composite mixtures of protein ligands of varying binding affinity and specificity for the same protein receptor; (ii) the development of rules and principles for the construction, composition, structure, and function of protein pore-based sensors that contain either a human Ras GTPase or a Raf Ras binding domain (Raf RBD) effector, a serine/threonine-specific protein kinase; (iii) the detection of PPI using guanine nucleotide exchange factors (GEFs), Ras GTPase activating proteins (GAPs), and alternate frame folding (AFF) switch mechanisms; (iv) the identification and quantification of oncogenic Ras-Raf interactions using samples in clean solutions and lysates of mammalian cells. These selective sensors could represent the basis for a nanoproteomics platform or might be further developed to create tools for high-throughput biomarker screening and protein profiling in blood, biopsies, and cell lysates.


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 = $0 )
2025	2022	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	13	3/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $297,419 )
2022	2022	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	13	7/21/2022	NON-COMPETING CONTINUATION	$297,419
														Subtotal = $297,419

Issue Date FY: 2021 ( Subtotal = $297,419 )
2021	2021	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	12	8/4/2021	NON-COMPETING CONTINUATION	$297,419
														Subtotal = $297,419

Issue Date FY: 2020 ( Subtotal = $349,738 )
2020	2020	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	002	11	7/31/2020	NON-COMPETING CONTINUATION	$297,635
2020	2020	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	001	10	6/22/2020	SUPPLEMENT FOR EXPANSION	$52,103
2020	2017	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	9	5/2/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $349,738

Issue Date FY: 2019 ( Subtotal = $312,612 )
2019	2019	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	10	8/1/2019	COMPETING CONTINUATION	$312,612
														Subtotal = $312,612

Issue Date FY: 2017 ( Subtotal = $298,993 )
2017	2017	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	9	7/21/2017	NON-COMPETING CONTINUATION	$298,993
														Subtotal = $298,993

Issue Date FY: 2016 ( Subtotal = $298,993 )
2016	2016	SYRACUSE UNIVERSITY	SKYTOP OFFICE BUILDING	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	8	7/28/2016	NON-COMPETING CONTINUATION	$298,993
														Subtotal = $298,993

Issue Date FY: 2015 ( Subtotal = $285,866 )
2015	2015	SYRACUSE UNIVERSITY	SKYTOP OFFICE BUILDING	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	001	7	8/20/2015	NON-COMPETING CONTINUATION	$285,866
2015	2014	SYRACUSE UNIVERSITY	SKYTOP OFFICE BUILDING	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	6	11/18/2014	COMPETING CONTINUATION	$0
														Subtotal = $285,866

Issue Date FY: 2014 ( Subtotal = $286,435 )
2014	2014	SYRACUSE UNIVERSITY	SKYTOP OFFICE BUILDING	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	6	9/1/2014	COMPETING CONTINUATION	$286,435
														Subtotal = $286,435

Issue Date FY: 2013 ( Subtotal = $269,633 )
2013	2013	SYRACUSE UNIVERSITY	SKYTOP OFFICE BUILDING	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	5	9/17/2013	NON-COMPETING CONTINUATION	$269,633
														Subtotal = $269,633

Issue Date FY: 2012 ( Subtotal = $279,924 )
2012	2012	SYRACUSE UNIVERSITY	SKYTOP OFFICE BUILDING	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	4	8/27/2012	NON-COMPETING CONTINUATION	$279,924
														Subtotal = $279,924

Issue Date FY: 2011 ( Subtotal = $280,397 )
2011	2011	SYRACUSE UNIVERSITY	SKYTOP OFFICE BUILDING	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	3	8/26/2011	NON-COMPETING CONTINUATION	$280,397
														Subtotal = $280,397

Issue Date FY: 2010 ( Subtotal = $283,671 )
2010	2010	SYRACUSE UNIVERSITY	SKYTOP OFFICE BUILDING	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	2	8/27/2010	NON-COMPETING CONTINUATION	$283,671
														Subtotal = $283,671

Issue Date FY: 2009 ( Subtotal = $286,948 )
2009	2009	SYRACUSE UNIVERSITY	SKYTOP OFFICE BUILDING	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	1	9/24/2009	NEW	$286,948
														Subtotal = $286,948

Grand Total All Awards = $3,828,048

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Engineered Nanopores for Single-Molecule Stochastic Sensing

Award Number: R01GM088403

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: 09/28/2009

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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