Wei Cheng, PhD - US grants

DESCRIPTION (Provided by the applicant) Abstract: Through infection of CD4 positive (CD4+) T lymphocytes, the Human Immunodeficiency Virus type 1 (HIV-1) has claimed twenty-five million lives since its discovery in 1983. Although it has been well established that HIV-1 initiates a T cell infection by binding to CD4 and chemokine coreceptors on the cell surface, the early events in HIV-1 infection of CD4+ T cells remain poorly understood. A variety of different techniques have been used over the years to study mechanisms of HIV-1 entry. However, one technical limitation that is inherent in all these methods is the inability to track the fate of a single HIV-1 virion from the very beginning of viral entry to chromosomal integration. In all these experiments, a population of viruses and cells were incubated and measured. Because each entry event can lead to proviral DNA integration with a finite probability, it is therefore difficult to establish a causative link between entry pathway and productive infection. The goal of this project is to develop a set of nanoscopic and novel technologies that we can harness to define the pathway and interactions by which HIV-1 infects CD4+ T cells. We are developing a technique based on optical tweezers that can manipulate a single HIV-1 virion, deliver it to CD4+ T cell and thus allows us to determine the fate of CD4+ T cell upon entry by a single virion. This technique will allow us to unambiguously define the molecular mechanisms of HIV-1 infection. Furthermore, we propose to measure directly the interactions between a single HIV-1 virion and receptors in the context of a live T cell. Collectively, these studies will contribute to a definitive and quantitative understanding of early events in HIV infection, which may help therapeutic development that is aimed to block HIV-1 entry to CD4+ T cells. The techniques developed herein can be useful for studying cellular uptake of not only viruses but other molecules, macromolecular assemblies and nanoparticles, and are applicable to a wide-range of ligand-receptor interactions on the cell surface. Public Health Relevance: The early events in HIV infection of CD4+ T cells are poorly understood. This proposal aims to develop a set of nanoscopic and other novel techniques to study HIV infection of CD4+ T cells in real time, one virion at a time. If successful, the results from this study will establish for the first time a causative link between HIV entry pathway and the productive infection of CD4+ T cells, which will help therapeutic development that is aimed to block HIV-1 entry to CD4+ T cells.

With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Professor Wei Cheng at University of Michigan and his group will develop an ultrasensitive technique that allows manipulation and visualization of a biochemical reaction, one molecule at a time. They will use this technique to study how ATP is consumed for base pair unzipping in a helicase-catalyzed reaction. 2% of the eukaryotic genome encodes helicase proteins. These proteins are ubiquitous and use ATP to unzip DNA or RNA so that genetic information is accessible for further processing. However, the mechanism of how these enzymes use ATP for bp unzipping remains poorly understood. This project focuses on the development of a single-molecule technique to simultaneously manipulate and visualize the reaction of hepatitis C virus NS3 protein, a model helicase. The success of this technique can lead to fundamental knowledge in our understanding of helicase mechanism, and allows quantitative measurement of a broad range of biochemical reactions in exquisite detail.

The broader impacts of this project involve research and teaching activities that aim to emphasize the importance of technical innovation in advancement of science, particularly to students with interests in biochemistry and biophysics. Professor Cheng proposes to teach biochemistry classes with emphasis on technical innovation that enabled important scientific discoveries. Moreover, he plans to establish an annual single-molecule showcase in his lab, which will be open to local high school and college students. Through simple demonstration experiments and hands-on experience, he hopes to inspire the students' interest in basic science.

Location Based Service (LBS) is one of the most popular types of applications in mobile networks. As the name suggests, the success of an LBS application depends on two pipelined procedures: localization and information transmission. In other words, an LBS application cannot start until all the mobile users have obtained their positions. The localization time of current methods is too long to support time-critical applications based on mobile networks, where users continually change their positions. This project envisions a radically new alternative to the intuitive pipelined procedures approach, where the LBS application can start before all the users? positions become available.

The intellectual merit lies in the concept of mobile essential localization, which is expected to significantly reduce both (i) localization time and (ii) energy consumption, while enhancing the location privacy and guaranteeing the success of LBS applications. The proposal entails high-risk as it is applied to real-time environments, which are highly unpredictable and dynamic. If successful, this novel paradigm could motivate scientific investigations aimed at a plethora of time-critical mobile network applications. One can expect high-reward in terms of applicability to areas of strategic interest including social and vehicular networks, and performance enhancements of such applications.

The broader impact of this project is reflected in several aspects: (i) The outcomes of this NSF project will have societal impact on facilitating the spread of mobile network usage; (ii) The new approaches may be adopted by US-based industry in their future designs and protocols for enhancing the location based service availability and its integrity; (iii) This EAGER projects investigates the time critical localization challenge from an interdisciplinary perspective combining Computer Science, Theoretical Computing, Electronic Engineering, and Communications; (iv) The resulting software codes will be disseminated to the public under open source license; and (v) New interdisciplinary graduate curriculum will be offered to students in MA/OH including minorities and underrepresented groups. Demos will be offered to Toledo Public School students.

Environmental awareness is a key to sustainable ocean monitoring and exploration. To meet the ever growing requirements of the ocean monitoring and exploration applications, and to preserve a sustainable blue ocean for next generations, a cognitive acoustic underwater network (CAUNet) that is aware of the coexistence of multiple underwater acoustic systems will be designed. The project goals include investigating acoustic spectrum usage via data collection and analysis, designing algorithms, software and hardware for acoustic spectrum sensing and spectrum management, and evaluating the feasibility and performance of the proposed work via simulations, and lab and field experiments.

This project will make significant contributions to the underwater network research community by improving the efficiency of UANs while making them more environmentally friendly. The research activities in this project also provide a rich environment and platform that can facilitate educating and training students from high school to graduate level and inspire students in underrepresented groups to pursue research in science and engineering. Moreover, this project will motivate and enable a wide range of research and outreach activities within the underwater communications, networking, engineering, and marine science communities, and promote progress towards practical solutions in diverse aquatic applications.

The Location Based Service (LBS) is one of the most popular types of applications in networking systems. As the name suggests, the success of a LBS application depends on two pipelined procedures: localization and information transmission. Unlike in relatively static networks, it is crucial to accomplish localization as early as possible in networks where users continually change their positions. This is to ensure that the targets' positions are still valid for LBS applications. In the environments, where GPS is not available (interfered, blocked, or destroyed), such as in battlefields, underwater, tunnels, and buildings, the current relative localization techniques are facing long localization delays, and this drawback cannot be overcome because of the nature of conventional localization requirements. Customers who have critical time requirements on location-based applications have to densely deploy anchor/reference nodes, which already know their locations, to reduce the localization time. However, the deployment of anchor/reference nodes is expensive, and it sometimes still cannot meet the critical time requirements. The proposed innovation, therefore, will provide solutions for those customers who have time-critical location based applications running in GPS free environments.

The goal of this I-Corps Teams project is to develop a feasible plan to commercialize the rapid localization techniques and develop a team to be capable of executing the plan. A team consisted of an academic researcher, a minority entrepreneurial lead, and an experienced minority and female industry mentor will closely work on business models, marketing, and seeking funding. The project intellectual merit lies in a novel design of the rapid localization platform. If successful, there will be a high-reward of applying the platform to many areas to improve their location based applications: availability, accuracy, integrity, and efficiency. The PI expects the market to be significant with revolutionary changes from existing ones and emerging new applications. The proposed innovation can be adopted by the industry and the military in their future designs and protocols for enhancing location-based services availability and integrity. The team expects the market to grow with revolutionary changes from existing applications and emerging new applications. The team will also keep improving/adjusting the technique while interviewing potential customers based on their feedbacks, needs, and data collected. The relevant products which may result from the proposed innovation may include protocols, systems, add-ons, licensing, and services.

PROJECT SUMMARY B cell responses to particulate antigens Two biophysical attributes shared by most animal viruses are the display of viral-specific proteins at certain densities on the surface of individual virions and the encapsulation of viral genome inside the virion. A threshold density of viral surface proteins is important to ensure efficient viral infection of host cells. From the perspective of the host, a threshold density of viral surface proteins may also be critical for the recognition by germline B cells for efficient mounting of humoral responses. The encapsulated genetic material may also stimulate B cells through the Toll-like receptors. Substantial mechanistic studies at the single-molecule level and imaging of live cells have revealed the sensitivity of B cells to the density of antigens. However, at the mechanistic level, it remains largely uncharacterized how B cells may recognize and respond to the collective attributes of a virus, including the spatial density of proteins and the internal nucleic acids. This project aims to test both functional and mechanistic relevance of viral features on B cell responses by developing quantitative assays both in vivo and in vitro. The success of this project will yield important mechanistic insights on how B cells may recognize particulate antigens similar in size to viruses and vaccines, and what are the possible functional outcomes of B cells in response to the recognition of these antigens.

The rapid development and rollout of mobile infrastructure and applications not only bring convenience to people's daily lives, but also give birth to threats that can jeopardize each individual's privacy and national security. Therefore, it is critical to train and educate the future workforce on the fundamental aspects of mobile security relevant to advanced cyberinfrastructure, and to improve their ability to identify, prevent, and respond to emerging threats. This project designs and develops a wide variety of intriguing and challenging hands-on laboratories that aim to create Eureka Experiences in reference to the "aha!" moment of understanding a previously incomprehensible concept. Such an illuminating learning experience is created by incorporating Inquiry-Based Learning (IBL) activities to hands-on laboratories. Overall, this project meets the pressing and essential needs in the Computer Science and Information Technology curricula, has a strong impact on developing the future workforce' core competencies and preparedness in mobile security related to advanced cyberinfrastructure, and helps advance national security.

In this project, three types of hands-on laboratories are designed and developed: i) Exploratory; ii) Core; and, iii) Advanced. The primary purpose of exploratory labs is to spark the interests of high school and community college students from diverse backgrounds to pursue a career in cybersecurity in mobile ecosystems related to advanced cyberinfrastructure. Core labs help prepare both undergraduate and graduate students in STEM for productive cybersecurity careers by enabling enduring understanding of key security concepts and technologies through hands-on practice in an interactive setting. Advanced labs assist future research workforce development by not only introducing emerging security technologies and threats, but also inspiring student research in related fields. In addition, a universal lab platform that is affordable and flexible is designed and developed. This project helps develop core competencies in a number of areas relevant to advanced cyberinfrastructure including how to secure mobile devices and wireless systems, protect large scale and streaming data from mobile and other sources, ensure user privacy, and prevent intrusion. By engaging all stakeholders during the development process, this project increases the likelihood of wide adoption of the developed materials by academic and professional communities.

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.