Immunosenescence is the complex process of immune disregulation associated with advancing age. In humans, the compromised immunity with aging is realized in an increased susceptibility to viral and bacterial infections, reactivation of latent viruses, and decreased responses to vaccines. It is well known that the adaptive immune system such as T and B-cell progressively deteriorate with advancing age. Cytokines are secreted regulatory proteins and play vital roles in controlling cell survival, growth differentiation and function.
The multi-disciplinary and tri-institutional "Linked Collaborative Research- Interdisciplinary Proposal" brings together several research groups with broad expertise and research interest to conduct experimental and theoretical studies aimed at engineering of novel nanostructures for sensing and high resolution imaging of cytokines. The group at the University of Michigan lead by Dr. Kotov will carry out the materials and nanotechnology aspect of this project, while the investigation at the University of Texas Medical Branch lead by Dr. Motamedi will concentrate on imaging and proteomics of this work. The experimental efforts of these groups will be complemented by the theoretical and modeling efforts of Dr. Govorov at Ohio University who will be developing models capable of predicting the response of the sensors. Specifically, they propose a novel sensing nanotechnology to image cytokines gradient of macrophages for the immunosenescence study of innate immune system. Successful demonstration of the versatile NW superstructure with cytokine-dependent frequency shift during the next three years allocated for this proposal will establish a concept and protocol for sensing and imaging of various cytokines while providing a unique opportunity to characterize the secretion of various cytokines from different age groups of macrophages, and developing the fundamental foundation for engineering of a new class of optical sensor for detection and imaging of various proteins.
Broader Impact
The proposed work is inherently multidisciplinary. The project combines expertise in new materials, imaging, bioengineering, biophysics and modeling as well as proteomics. From educational point of view, PIs, and graduate students will be immersed into a highly diverse environment, learning to interact and communicate effectively with professionals in several different fields of science and engineering. Special attention will be given to providing research opportunities to undergraduates and minority. The goals and scope of the interdisciplinary research (IDR) program at NSF appear to be an exact match for the proposed research. The joint efforts of the proposed multi-disciplinary team will create a powerful tool for the fundamental understanding of cell biology, characterization of proteomics of many diseases, clinical diagnosis of cell-secretion related diseases and the potential for rational control of cell differentiation in tissue engineering using novel optical sensors to detect and monitor the spatial and temporal distribution of small molecules such cytokines using high resolution imaging techniques. The proposed research combines the synergistic activities of a chemist and engineer with expertise in material sciences, nanotechnology, nanophotonics and sensing (Dr. Kotov, U of M), a bioengineering team specializing in cellular and biomedical imaging working with internationally known expert in the area of proteomics and inflammatory responses (Dr. Motamedi and his collaborators at UTMB) and a biophysicist and modeler with expertise in modeling of complex nanostructure and their behavior. The proposed joint efforts will significantly advance fundamental knowledge in multiple engineering and life science areas, including sensing, imaging and proteomics and if successful could have enormous long-term impact on health care and our national needs.
Immunosenescence is the complex process of immune deregulation associated with advancing age (aging). As we get older the compromised immunity with aging is realized in an increased susceptibility to viral and bacterial infections, reactivation of latent viruses, and decreased responses to vaccines. A part of this processes of aging is the change in regulatory functions of cytokines -- secreted regulatory proteins that play vital roles in controlling cell survival, growth differentiation and function including those of immune cells. This multi-disciplinary and tri-institutional "Linked Collaborative Research- Interdisciplinary Proposal" brought together several research groups with broad expertise and research interest to conduct experimental and theoretical studies aimed at engineering of novel nanostructures for sensing and high resolution imaging of cytokines. The group at the University of Michigan lead by Dr. Kotov engineered the nanoparticle assemblies capable of sensing cytokines with high sensitivity and fidelity. The investigation at the University of Texas Medical Branch lead by Dr. Motamedi concentrated on their application to imaging. Theoretical and modeling efforts of Dr. Govorov at Ohio University resulted in predictive models necessary to describe the response of the sensors. As the result of this project, a novel sensing nanotechnology to image cytokines gradient of macrophages was developed. The concentration and gradient of cytokines was measured by the emission frequency shift sensors, stemming from exciton-plasmon interactions upon nanocolloidal superstructures of nanoparticles (NP) and nanowires (NW) connected by molecular springs of poly ethylene glycol (PEG) (See Figure). PEG chain acts as a "molecular spring" that expands and contracts when the target protein is attached or detach respectively. Such sensor design can be realized for cytokines and any other regulatory proteins in the body. The research work was complemented by intense educational and outreach duties. On the University of Michigan side, the Prof. Kotov developed a new class for undergraduate and graduate students aimed at biomedical applications of nanostructures. He was also actively involved in the transit to practice the cytokine detection in 3D cell cultures that is currently being used to test drugs. He was also working on dissemination of the knowledge about advances in nanotechnology in biomedicine to students of public elementary, middle, and high schools in Ann Arbor Michigan and Detroit. He was also mentoring students from "Neutral Zone" the safe-environment club for teenagers in Ann Arbor MI.
