Cells Never Rest: Kudos to Cellular Signaling Pathways
The human body is composed of trillions of cells, the basic building blocks of all living things. Our cells perform many diverse functions, including converting nutrients from food into usable energy, promoting growth, and preventing infection and disease. Each of these cellular functions involves a series of coordinated biochemical reactions and, in order for cells to function efficiently, they must “know” which reactions to “turn on” and which ones to “turn off” in the face of an everchanging environment. Importantly, failure to properly coordinate these activities underlies many pervasive diseases, including cancer, diabetes, cardiovascular disease and Alzheimer’s disease.
How do cells know what to do and when to do it?
This is the subject of Dr. Robert Newman’s research. Newman, an associate professor in the Department of Biology at North Carolina Agricultural and Technical State University, is interested in understanding the organization and regulation of cellular signaling pathways, with a particular emphasis on phosphorylation-dependent signaling pathways mediated by protein kinases and phosphatases.
A cellular signaling pathway is exactly what it sounds like. A typical cellular signaling pathway is composed of an array of signaling molecules, including small molecule second messengers (such as calcium ions or cyclic AMP) and various types of signaling enzymes (such as protein kinases and small G-proteins), acting in a coordinated fashion to process information about the cellular environment. However, these signaling pathways do not operate in isolation. In fact, hundreds of intersecting signaling pathways are operating simultaneously to process information about both the cell’s external environment and its internal state. Moreover, the same signaling molecule(s) are often involved in multiple cellular signaling pathways. For instance, a given signaling enzyme, such as one of the 518 protein kinases encoded in the human genome, might play a role in regulating diverse cellular processes, such as cell proliferation and programmed cell death. A major question in the signaling field is how cells are able to selectively activate one signaling pathway (e.g., a pathway leading to cell proliferation) while not activating another (e.g., a pathway leading to cell death) even though key signaling molecules are shared between the two pathways.
Dr. Newman’s group is exploring the hypothesis that, by modulating the substrate selectivity of protein kinases, the cell is able to control which “arm” of a branched pathway is activated in response to a given signal.
Protein kinases, which are key components of nearly all cellular signaling pathways, catalyze the transfer of a phosphate group from a high-energy, phosphate-donating ATP molecule to specific substrates (a substrate is the material upon which an enzyme acts). As you might recall from biology class, this process is known as “phosphorylation”; the substrate gains a phosphate group while the high-energy ATP molecule donates a phosphate group. Inside the cell, phosphorylation can impact a protein’s cellular function in several related ways. For instance, phosphorylation can alter a protein’s stability, protein-protein interactions, enzymatic activity and/or sub-cellular localization. Thus, by regulating the phosphorylation status of cellular proteins, protein kinases play a critical role in the regulation of nearly all cellular processes, including replication, cell growth, metabolism, and cell death.
Dr. Newman was recently awarded a $1.4M grant from the NIH National Institute of General Medicine Sciences to better understand how redox modification (i.e., modulation of a protein’s oxidation state) of select protein kinases alters their substrate selectivity. The four-year project, entitled “Analysis of Redox Modification on Kinase Substrate Selection: Molecular Mechanisms and Cellular Consequences”, plans to investigate the biochemical mechanisms underlying oxidation-induced shifts in protein kinase substrate selection and to begin to explore the functional consequences of redox modification on kinase-dependent signaling processes inside cells.
Newman’s research, which has the potential to answer fundamental questions about the regulation of cellular signaling pathways, will identify points of signal integration between redox- and phosphorylation-dependent cellular signaling pathways. This information can be used to develop computational models of cellular signaling pathways to predict dynamic changes in pathway properties following exposure to various physiological, pharmacological and toxicological stimuli, both in isolation and in combination. His team also hopes to complement existing models of pathological oxidative stress and provide new opportunities for targeted therapies for many diseases, such as cancer, diabetes and cardiovascular disease.
“Love Your Gut”
Dr. Marc Cook is an assistant professor in the Department of Human Performance and Leisure Studies in the College of Health and Human Sciences. He is studying how exercise and dietary choices impact specific gut bacteria, resulting in better cardiovascular health outcomes.
Unless you’ve been living under a rock the last few years, you have probably heard the discussions surrounding gut bacteria. Clinically known as “microbiota”, these terms reference the microbe population which lives in the human intestine. Now supported by a stocked shelf of over-the-counter pro-biotics, ensuring the health and survival of gut microbiota is big business, and big science for researchers like exercise physiologist and immunologist Dr. Marc Cook.
Gut microbiota is comprised of trillions of microorganisms; over 1000 different species of known bacteria with more than three million genes! If you took out the average adult’s gut microbiota and put it on a scale, it would weigh over four pounds! About a third of your gut microbiota is common to most people, but two thirds are unique to you. While each of us has a unique microbiota profile, it fulfils the same physiological functions: it aids in digestion, helps with the production of vitamins, helps us combat harmful microorganisms, and plays an important role in the development and maintenance of our immune system.
Healthy and balanced gut microbiota is key to good health, and Dr. Marc Cook is working to give N.C. A&T athletes and individuals with high blood pressure a glimpse into the inner-workings of their bellies. “African Americans experience hypertension at a higher rate than people of other races,” explains Dr. Cook. “This racial health disparity, and the role of specific gut bacteria have in cardiovascular health, is the subject of my research. We can utilize exercise to better understand which gut microbes are associated with better blood pressure.”
Some beneficial bacteria in the human gut produce what are called short-chain fatty acids. These have been shown to aid in maintaining a health blood pressure and a host of other immune responses with anti-inflammatory benefits. By examining factors affecting the amount of bacteria, and the number of short-chain fatty acids present in the blood and a person’s blood pressure readings, Dr. Cook is starting to understand how different populations of microbes can take active measures to improve their health.
“Here’s what we know so far. Exercise increases bacteria that produce short-chain fatty acids in the gut. A diet high in fiber energizes short-chain fatty acid bacteria. The more active our beneficial gut bacteria are, the more short-chain fatty acids are produced, resulting in lower blood pressure and therefore decreased risks for cardiovascular disease, various cancers, and other ailments. An active short-chain fatty acid producing gut translates into better health, so I am engaging populations that are intentionally and unintentionally impacting their gut bacteria.”
Dr. Cook has secured research funding from the American Heart Association, the Unites States Department of Defense and the North Carolina Translational and Clinical Sciences Institute. He is working with populations of athletes (who are energizing their gut bacteria through exercise) as well as a group of adults 18-50, whom have normal and high blood pressure. Each study uses a combination of exercise techniques, a diary of food intake, as well as gut microbial bioinformatics achieved through different tests and measurements.
Dr. Cook’s research will help us understand how different populations, particularly African Americans, can take active steps toward energizing gut bacteria to benefit their cardiovascular health. “Your gut is unique to you, and how well you understand it and support it will play an enormous role in your health and ability to both avoid and fight disease.”
N.C. A&T’s Dr. Suzanne O’Regan Part of Team Using Big Data & Artificial Intelligence to Advance Disease Prevention
Through a new $2 million National Science Foundation grant, scientists at the Cary Institute of Ecosystem Studies, the University of Georgia, and North Carolina A&T State University are harnessing the power of machine learning to forecast outbreaks of zoonotic disease.
Each year, more than a billion people become sick from Ebola, Zika, SARS, and other pathogens acquired from wildlife, livestock, and other animals. Prevention relies on an ability to predict when and where pathogens are likely to make the leap from animals to people.
Barbara Han, a disease ecologist at the Cary Institute, is leading the five-year study. She explains, “We want to help shift society from a reactive to a proactive approach to managing zoonotic disease. Instead of responding to outbreaks, let’s try to stop them from happening in the first place. Using big data as a potential surveillance tool is an exciting new step toward prevention.”
Funding will enable the team to bring together information on pathogens, potential animal hosts, and environmental factors known to facilitate disease transmission, with the goal of developing innovative methods of mapping when and where the next major zoonotic disease outbreak might occur.
John Drake of the University of Georgia explains, “We are creating models which draw ‘boundaries’ around which species can host which pathogens, which pathogens can pass from animals to humans, and what combination of environmental factors facilitate spillover and human-to-human transmission. On the basis of these biological properties, we can pinpoint where disease emergence is possible.”
Phase one of the study involves building predictive statistical models that will help the researchers identify traits common among animals that carry disease, and pathogens and parasites that cross the species barrier. “We are looking at data that describe hosts, pathogens, and their environments, to determine which combinations of these features presage disease being realized on a global landscape,” Han says.
Models are built using extensive data sets on the physical and life history traits of host species and known pathogens. Host-pathogen pairings are then linked to the geographical locations with suitable environmental conditions. Also considered are conditions surrounding documented disease outbreaks to determine what factors were at play when that disease broke out.
Suzanne O’Regan of North Carolina A&T State University explains, “By using data that is global in scale, we are seeking to reveal generalizable features of ‘good’ disease carriers. Over 50 life history features are being incorporated into models for most mammal groups.” This includes data on animals’ physical characteristics, metabolic and reproductive rates, range of diet, and timing of daily activity – whether the animal is primarily active during the day, at night, or at dawn and dusk.
On the pathogen side, the team is interested in: whether a pathogen is able to survive in a given host and environment, the mechanism by which the pathogen is transmitted between hosts, and whether it exhibits sustained transmission between people – as opposed to a single ‘dead-end’ transmission from animal host to human.
Environmental features broadly consider temperature, precipitation, seasonality, and biome. The study will also encompass country-specific socioecological factors such as GDP, public health infrastructure, and investment in research and healthcare – all of which bear important implications for how effectively a country can manage disease prevalence and respond to an outbreak.
The second subproject will investigate how diseases move dynamically within a system. Once the traits of hosts, pathogens, and their environments – and the relationships among them – are known, the team will incorporate these into mathematical models to reveal how disease dynamics might play out in animal populations over time. This approach accounts for traits such as lifespan and rate of reproduction, which directly impact how fast a pathogen can spread via a particular host.
Han explains, “The novelty of this work is in bringing biological realism via machine learning into a classic body of theory, leveraging large sets of biological data available to us. These tools merge data mining and machine learning with established methods of studying disease dynamics to help us think carefully about what’s distinguishing animal groups from each other in terms of zoonotic disease, and eventually, for risk of human spillover and epidemics.”
The team also plans to use the models and techniques developed in this project to respond to zoonotic disease outbreaks that might occur during the course of the study.
N.C. A&T and Industry to Bring Novel Aspirin Derivatives to the Marketplace
Patients who require the benefits of aspirin without the accompanying stomach irritation are a step closer to comfort and cures with the signing of an exclusive licensing agreement. Dr. Shengmin Sang, a food scientist with North Carolina Agricultural and Technical State University, licensed his patent for a family of novel aspirin-derived compounds to SARISA Therapeutics, an Invenshure Company out of Minneapolis, Minn. Sang’s patented compounds may be useful in treating or preventing colon cancer, heart disease and other disorders. Through this commercialization effort, more patients may be able to receive the benefits of aspirin without incurring adverse side effects.
“The timing of this agreement couldn’t be better for patients,” explains SARISA Therapeutics CEO Danny Cunagin. “Last April, the U.S. Preventive Services Task Force added colon cancer to the list of diseases for which aspirin should be prescribed as a preventive treatment. We aim to make Dr. Sang’s discoveries available to all patients who need aspirin’s therapeutic usefulness minus its gastric irritation side effects.”
Dr. Sang, a professor and lead scientist for functional foods in the College of Agriculture and Environmental Sciences, developed the new compounds at N.C. A&T’s Center for Excellence in Post-Harvest Technologies. “It is gratifying when our hard work is proven capable of improving people’s lives,” said Sang. “Our discoveries could be helpful in treating anything for which aspirin is recommended for treatment or prevention. Through our research we have found it to be less toxic to the stomach than regular aspirin.”
Tests on colon cancer cell lines showed that Sang’s novel compounds, containing both aspirin and bioactive phytochemicals, were more effective at inducing cancer cell death than any of the individual components used alone or physically mixed. Sang describes his findings in the studies, “Novel Resveratrol-based Aspirin Prodrugs: Synthesis, Metabolism and Anticancer Activity,” published in the Journal of Medicinal Chemistry, and “Gastroprotective -Gingerol Aspirinate as a Novel Chemopreventive Prodrug of Aspirin for Colon Cancer,” published in Scientific Reports. Funding for this, and other studies that gave rise to his patent and this commercialization agreement, came from the National Institutes of Health and the North Carolina Biotechnology Center.
The Center for Outreach in Alzheimer’s, Aging and Community Health at N.C. A&T Receives $2 Million Grant from the Merck Foundation
The Center for Outreach in Alzheimer’s, Aging and Community Health (COAACH), a university-sponsored Center addressing literacy, care management, training and research in Alzheimer’s and other aging related diseases such as diabetes, announced it has been awarded a $2 million grant from the Merck Foundation to expand the capacity, operations and sustainability of the Center. Merck’s financial support will extend COAACH’s ability to solidify local and state-level partnerships, educate and engage North Carolina’s most vulnerable populations and create a sustainable model for community-based support.
Building upon a 2013 gift from Merck, which helped to establish the Center, this latest financial commitment will enable COAACH to establish a Caregiver College to extend education opportunities, implement a Lay Health Advisor Model of Care to broaden outreach into underserved patient and caregiver populations, and create a Family Navigation Program to augment its current early detection and care management programs.
“The Center is extremely grateful to the Merck Foundation for its ongoing support to this university, but more importantly to the aging residents and caregivers in North Carolina who need and deserve our support,” said Dr. Goldie Byrd, the Center’s interim director. “With Merck’s continued financial participation, we are able to build upon past success, and further impact education and outreach, community engaged research and health policy in North Carolina.”
The Center for Outreach in Alzheimer’s, Aging and Community Health promotes healthy aging for all communities. It provides education, community empowerment and evidence-based research so that individuals, particularly the most vulnerable, can live life with quality, dignity, and independence. The Center sponsors numerous education and training activities such as its monthly Lunch ‘n Learn Series, frequent patient assessment opportunities, support groups, conferences, and other valuable caregiver resources. In 2016 COAACH held its 8th Annual Caregivers Education Conference. It also conducts research in Alzheimer’s genetics and community engagement projects. Please learn more About COAACH at www.coaachhealth.org.
About The Merck Foundation
The Merck Foundation is a U.S.-based, private charitable foundation. Established in 1957 by Merck, a global health care leader, the Foundation is funded entirely by the company and is Merck’s chief source of funding support to qualified non-profit charitable organizations. Since its inception, the Merck Foundation has contributed more than $870 million to support important initiatives that address societal needs and are consistent with Merck’s overall mission to help the world be well. For more information, visit www.merckgiving.com
N.C. A&T’s Clinical Immersion Experience
Five N.C. A&T students spent two summer weeks at UNC hospitals and clinics in Chapel Hill, North Carolina, shadowing doctors and clinicians as part of A&T’s first Clinical Immersion Experience. Kierra Fleming, Lauren Florence, Marlayna Jackson, Rina Mudanyi and Jerria Turner, all bioengineering or chemical engineering students at A&T, witnessed firsthand the clinical needs of physicians, rehabilitation professionals and nurses as they relate to bioengineering applications. Dr. Matt McCullough, associate professor in the Department of Chemical, Biological and Bioengineering founded the immersion program through a grant from VentureWell. The students will apply knowledge gained during the clinical experience in their upcoming year-long capstone course experience.
Jerria Turner, a senior biomedical engineering student from Chesterfield, Virginia, participated in the program. “I first learned about the clinical immersion experience from McCullough. As he told me more about it, my interest grew because I had always wondered about the clinical side of biomedical engineering applications, and I knew this experience would provide answers for me.”
Turner said it was time well spent. “This experience definitely reassured me that I am pursuing and studying exactly the right things. I am more confident than ever about my chosen path, because I know the topics that my peers and I are researching and studying in class are preparing us to be individuals that will change and improve the lives of many in the future. I definitely see myself working in the clinical field. I loved meeting and talking with the different patients. When you create something as an engineer you know it will help or improve someone’s life or their daily functions, but when you’re able to meet one of those people face to face, what you created means more. You believe in the positive impact of what you created or designed because you witness a human being benefitting from it.”