An NDSU faculty member has received $890,900 from the National Science Foundation (NSF) to support her research and educational programs at NDSU.
Sangita Sinha, assistant professor of chemistry and biochemistry has received a four year award from the NSF Division of Molecular and Cellular Biosciences. Currently, this is the only investigator-initiated NSF MCB award in the state of North Dakota.
Sinha determines the atomic resolution structure of proteins using X-ray crystallography in order to understand how different proteins perform their biological function. A detailed understanding of a protein’s structure is essential to understanding its mechanism, and is a central concept in Biochemistry. The Sinha laboratory, the first macromolecular crystallography laboratory in ND, combines X-ray crystallography, the most powerful method of protein structure determination, with multiple complementary biophysical, biochemical, molecular biology and cellular methods to obtain a comprehensive structure-based understanding of protein function.
The goal of the NSF grant is to understand the structure and mechanism of a protein called Beclin 1, which is a key component of the autophagy pathway.
Autophagy is an essential pathway responsible for the removal of unwanted or harmful cellular components to enable nutrient recycling. Autophagy occurs in all eukaryotic organisms, ranging from yeast to humans. Beclin 1 and autophagy are required for a range of critical organismal processes including embryonic development, tissue differentiation, cell-growth and surviving external and internal stressors such as free radicals and pathogens. Dysfunction of human Beclin 1 has been implicated in a wide range of human health issues including embryonic fatalities and developmental defects; reduced longevity; neurodegenerative diseases, especially Alzheimer’s disease; cancer; heart failure; and stroke. Many viruses such as herpesviruses, HIV and the influenza virus encode proteins that bind Beclin 1 to block autophagy, allowing the viral infection to continue. This underscores the importance of Beclin 1 and autophagy for our innate immune defenses. Thus, differential modulation of Beclin 1-mediated autophagy is a promising therapeutic target for diverse diseases.
Key work done by Sinha and coworkers has delineated the domain architecture, detailed structure and conformational flexibility of this protein. Beclin 1 appears to be a protein interaction hub as it binds to over twenty diverse cellular or viral proteins. Research in the Sinha lab is providing important insight into how this protein interacts with so many partners, by resolving the dynamics of Beclin 1 conformational flexibility and establishing the role of selected binding motifs. A structure-based mechanistic understanding of Beclin 1 function is key to understanding the role of Beclin 1 in various diseases, and eventually to designing therapeutics targeting Beclin 1 function to treat these diseases.
Yang Mei, a graduate student in the Sinha laboratory has been a key contributor to this research. In the future this research will involve a postdoctoral fellow, and several other graduate and undergraduate students.
Additionally, funds are provided for the creation of a new 3-credit, graduate-level course at NDSU (BIOC 600), to provide high school STEM teachers across the upper Midwest with a unique professional development opportunity. The objective of the course is educate high school teachers in the principles of biomolecular structure, and also provide them with pedagogical tools and resources to disseminate this information to their students. Ultimately, this will impact hundreds of students, far beyond the 4-year period funded by this grant. BIOC 600 is being offered for the first time as part of the North Dakota State University Distance and Continuing Education’s summer 2015 professional development program.
The research is funded by Award No. 1413525 from the NSF.
Sinha earned a doctorate in biochemistry and molecular biology from Purdue University. She then worked as a Howard Hughes Medical Institute research associate at University of Texas Southwestern Medical Center. She started as faculty in the department of Internal Medicine at University of Texas Southwestern Medical Center before moving to NDSU.