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NET CHARGE IN PROTEIN STRUCTURE AND AGGREGATION: A CHARGE LADDER APPROACH

Award Number: F32GM081055
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2007
PERIOD OF PERFORMANCE END DATE: 03/31/2009

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NET CHARGE IN PROTEIN STRUCTURE AND AGGREGATION: A CHARGE LADDER APPROACH - DESCRIPTION (provided by applicant): This proposal describes ongoing and future-planned investigations that seek to determine the role that net charge plays in biophysics-related problems. The first aim presents the hypothesis that a protein's net charge plays a significant role in determining the rate of amide hydrogen exchange in proteins - a reaction that is catalyzed by hydroxide anion at pH>4. Protein charge ladders and mass spectrometry are used to test this charge-dependent exchange hypothesis. The second aim of this proposal hypothesizes that protein aggregation, as related to many human diseases, can be inhibited with subtle chemical modifications that increase the protein's net charge. Controlling charge - as opposed to some other parameter or property such as native-state stability or structure - is an underemphasized and unexplored possibility in developing drug therapies for a wide array of diseases linked to protein aggregation. The experiments proposed in Aim 2 are intended as a proof of concept for this approach (termed PRO-CHAIN; PROtein CHarging for Aggregation INhibition). Aim 3 proposes experiments to explore if electrostatic interactions between proteins and surfaces can be used to i) promote ii) direct iii) pattern, or iv) inhibit protein aggregation onto charge- micro-patterned self assembled monolayers (SAMs). The aggregation of proteins onto charged surfaces, such as lipid membranes, is gaining acceptance as a likely scenario in disease pathogenesis. This third aim describes experiments using protein charge ladders, micro-contact printing and self assembled monolayers to explore this important phenomenon that is suspected to be relevant to a wide range of diseases. Relevance to public health: This proposal has immediate relevance to public health; first, it describes a whole new approach for developing drug therapies, referred to as PRO-CHAIN (PROtein CHarging for Aggregation INhibition), that may aid in the development therapies for the treatment of a wide range of protein aggregation diseases such as Alzheimer's disease and type II diabetes. Furthermore, this proposal describes research that may further our understanding of the molecular determinants of hydrogen exchange in protein folding studies -- many of these studies focus on pathogenic proteins that cause human disease. Lastly, this proposal uses new cutting edge technologies to study protein-surface interactions of the sort that may be related to numerous neurodegenerative diseases, as well as cancer.


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: 2008 ( Subtotal = $49,646 )
2008	2008	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	3/21/2008	NON-COMPETING CONTINUATION	$49,646
														Subtotal = $49,646

Issue Date FY: 2007 ( Subtotal = $46,826 )
2007	2007	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	3/5/2007	NEW	$46,826
														Subtotal = $46,826

Grand Total All Awards = $96,472

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NET CHARGE IN PROTEIN STRUCTURE AND AGGREGATION: A CHARGE LADDER APPROACH

Award Number: F32GM081055

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2007

PERIOD OF PERFORMANCE END DATE: 03/31/2009

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