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Award Detail

Doing Business As Name:University of Nebraska Medical Center
  • Yuri Lyubchenko
  • (402) 559-7456
Award Date:11/26/2019
Estimated Total Award Amount: $ 669,178
Funds Obligated to Date: $ 669,178
  • FY 2020=$669,178
Start Date:01/01/2020
End Date:12/31/2023
Transaction Type:Grant
Awarding Agency Code:4900
Funding Agency Code:4900
CFDA Number:47.074
Primary Program Source:040100 NSF RESEARCH & RELATED ACTIVIT
Award Title or Description:Collaborative Research: Theoretical and Experimental Investigation of Molecular Mechanism of DNA Synaptic Complex Assembly and Dynamics
Federal Award ID Number:1941049
DUNS ID:168559177
Parent DUNS ID:068662618
Program:Molecular Biophysics
Program Officer:
  • Jaroslaw Majewski
  • (703) 292-7278

Awardee Location

Street:987835 Nebraska Medical Center
Awardee Cong. District:02

Primary Place of Performance

Organization Name:University of Nebraska Medical Center
Cong. District:02

Abstract at Time of Award

Genome integrity is a crucial feature defining the successful functioning of cells, their maintenance, and evolution. The genetic processes in the cell require distant communications between the regulatory regions controlled by specific proteins. Mistakes in this interaction process result in termination of the genetic process followed by cell damage, disease development, or cell death. A common feature of these genetic processes is a transient formation of a complex between two DNA segments by specific proteins. However, a molecular model explaining how the proteins recognize specific DNA segments remains uncertain. The combined theoretical and experimental studies under this project are expected to build a novel framework, which will also explain how the search process of distant DNA segments in a long DNA molecule occurs. Several avenues that facilitate the integration of scientific and technological advances in education programs for graduate and undergraduate students are proposed. The concepts of DNA and single molecule biophysics are incorporated into a Biophysical Chemistry course for the UNMC program 'Graduate training in structural biology and biophysics'. These concepts are also included in Biophysical Chemistry and Chemical Kinetics courses that are taught at Rice University as well the participation in the project of undergraduate students from the University of Nebraska-Omaha (UNO) and nation-wide scholars from the UNMC Summer Undergraduate Research program. The PIs will participate in the Young Nebraska Scientists (YNS) program to provide STEM enrichment activities for middle and high school students and activities to attract the underrepresented minority undergraduate students Summer Research Program at Rice University. A large societal impact from this proposed project will be the training of postdoctoral fellows, graduate students, and undergraduate students at the university level. A critical step in numerous fundamental genetic processes is the protein-mediated assembly of a synaptic complex between distant DNA regions. The formation of a synaptic complex is a general phenomenon found in gene regulation (e.g., Lac repressor), site-specific recombination (e.g., Flp, Cre recombinases), and various genome integration systems. Still, little is known regarding the molecular mechanisms that underlie how such proteins search for DNA distant sites during the formation of synaptosomes. If the specific sites needed for the formation of the synaptosome are located on the same DNA molecule the search for the two sites leads to the formation of a loop in the DNA. However, the knowledge on the assembly of synaptosomes is very limited. A proposed comprehensive research plan fills this gap by generating a quantitative model describing the phenomena of the search of specific sites and the synaptosome assembly. This problem is approached by coordinated experimental and theoretical studies to be conducted by labs that specialize in experiments and theory. The central hypothesis behind this project is that sliding and intersegment transfer are the key pathways in the search for two and more sites; the partition between these two pathways specify the dynamics of the site search. The project objective is to characterize the role of DNA loops and other topological features that define the search process. Successful completion of the innovative work proposed herein will advance knowledge of fundamental processes involved in the DNA synaptosome assembly, which will in turn explain mechanisms involved in the genome rearrangements. The proposed experimental and theoretical approaches will lay a foundation to elucidate mechanisms of such fundamental genetic processes as site-specific recombination, integration, excision, and inversion of specific DNA regions within genomes. This project is supported by the Molecular Biophysics and Genetic Mechanism clusters of the Molecular and Cellular Biosciences Division in the Directorate for Biological Sciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

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