Spotlight on Research
UVM Researchers are hard at work developing treatments for a variety of diseases — from diabetes, cryptosporidiosis, and cancer to addiction, cystic fibrosis, and anxiety disorders. Animal models play a crucial role in understanding the development of these diseases and in searching for effective treatments.
Creating New Treatments to Control Diabetes
Type 1 diabetes affects one in every 600 children and can shorten a person's lifespan by up to 15 years. It's not a disease that sufferers can outgrow, and controlling it requires constant vigilance. Furthermore, it's a disease that is increasing in prevalence and, importantly, there is no cure. That's why endocrinology researchers at UVM are working on developing potential treatment strategies that may end the need for multiple daily insulin injections.
How are they doing this?
Researchers utilize mice to examine the factors that promote the growth and survival of pancreatic islet beta cells — the only cells in the body that secrete insulin. When a portion of the pancreas is surgically removed in mice, the islet cells in the remaining pancreas compensate by increasing in number and metabolic activity. The use of genetically modified mice, which lack specific proteins, has helped to understand how the growth and survival of these cells is regulated. In the future, this knowledge may be useful for developing treatments for type 1 diabetes.
Why are animals important?
Much of the current research on diabetes focuses on communication within and between cells and tissues in the body. The cascade of events associated with beta-cell growth and regeneration is complex and is only beginning to be understood. Living animals so far are the best means of studying the intricate "cross-talk" between multiple cell and tissue types.
What are the significant outcomes of this research?
About five percent of all cases of diabetes are Type 1 or "insulin dependent." The cause of type 1 diabetes is not known, but there appear to be both genetic and "environmental" components to the disease. Since there is no cure, patients must receive daily insulin treatments for life. Developing efficient and safe ways to either regenerate or transplant beta cells into the patient, or to prevent their destruction by the immune system, would have a significant impact on patients' longevity and quality of life.
Developing New Treatments for Cryptosporidiosis
The parasitic disease cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in developing countries and causes chronic diarrhea in AIDS patients. This parasite also is a common cause of diarrhea in calves on dairy and beef farms, resulting in deaths and impaired growth. There is no approved treatment for "crypto" in calves, and the only approved treatment for human patients is ineffective in malnourished children and immunocompromised people.
How are they doing this?
Researchers at UVM are working to identify potential new anti-cryptosporidial drug candidates. Drugs initially are screened using a tissue-culture-based assay to assess the ability of the drugs to inhibit the development or activity of the parasite. Promising candidates are then further screened using a mouse model of cryptosporidiosis. However, although mice can serve as a host for the parasite, they do not develop diarrhea or any clinical disease. So Holstein calves were chosen as an appropriate model to determine if new drugs could reduce the incidence of diarrhea or inhibit shedding of the parasite in the animals' fecal material.
Why are animals important?
The impact of cryptosporidia on patients is dependent on a number of different factors, including the host's immune function and nutritional status. Although cell culture can be used for initial screening of treatments, the complicated milieu of immune function, gastro-intestinal environment and host nutritional status cannot be replicated in a petri dish. Confirming that drug candidates actually alleviate clinical disease in animal models is critical prior to testing any drug in a human clinical trial.
What are the significant outcomes of this research?
This research strategy has identified at least one drug candidate that holds great promise for the treatment of cryptosporidiosis in malnourished children and immunocompromised patients. The drug also has potential for treatment of neonatal calves afflicted with this debilitating disease.
Developing Targeted Cancer Treatments
Researchers at UVM are hard at work developing "targeted" immunotherapeutic agents for cancer. Cancer cells often contain mutations which can be ideal targets for the development of vaccines. Antibody molecules which target specific cancer cells may be more effective than current treatments at fighting cancer, without the deleterious side effects of more “conventional” anti-cancer drugs.
How are they doing this?
Cancer researchers use next-generation sequencing to identify mutations in patients' tumor cells (collected by biopsy). Mutated peptides can then be developed into a vaccine and injected into mice. The goal is to induce the mice to make their own antibodies against tumor cells, effectively "vaccinating" the mice against malignant tumors. Alternatively, the antibodies may be made in cells outside of the mice and used as therapeutic agents in mice into which tumor cells have been transplanted.
Why are animals important?
These novel cancer therapies are initially tested in cell-culture systems. Only the most promising treatments or combinations of treatments are tested using animal models. However, before any treatments can be utilized in human beings, it is important (and required by the U.S. Food and Drug Administration) to observe how the therapies work in a whole-animal system. Even though scientists can learn a great deal using cell-culture systems, we still do not have the ability to replicate the complex environment of a living animal, with multiple organ systems, in culture.
What are the significant outcomes of this research?
Targeted cancer treatments are of particular value because they direct their activity against the specific cancer cells and spare non-cancerous cells. Many cancer treatments currently in use are toxic to rapidly multiplying cells. Although tumor cells are affected, so are other rapidly dividing cell types in the body. This broad toxicity is responsible for many of the devastating side effects of cancer chemotherapy. Targeted treatments will significantly improve cancer patients' quality of life.
Looking at Learning and Drug Addiction
Pioneering work in UVM's Department of Psychology — connecting neural events and human behavior — has made our researchers in-demand speakers and contributors to journals where they translate basic experiments into insights that may lead to better treatment for issues like anxiety disorders and drug addiction.
How are they doing this?
Extinction learning — the process, for example, of teaching a dog that a bell no longer means food — inhibits original learning but doesn't erase it. Our researchers have discovered that extinction learning is dependent on the context or environment in which it is learned. So when a person leaves the therapist's office or rehab clinic, the lurking habit, fear, or addiction becomes the default, explaining the prevalence of relapse. Using rats, researchers space exposure trials at different intervals, teaching the rats a rhythm of sorts, then test when or whether the rats achieve extinction.
Why are animals important?
The study of behavior in animals cannot completely replace studies in humans. However, scientists can examine the neurological mechanisms of learning under a much more controlled environment in animals (for instance, diet, activity level, and light cycle can be controlled in animals much more easily than in humans). In addition, animals can be utilized for studies of unhealthy behavior (such as nicotine or alcohol addiction) in ways which would not be ethically tenable in human subjects.
What are the significant outcomes of this research?
Understanding ways that individuals can "unlearn" unhealthy behaviors may allow people to more easily stop smoking, control alcohol addiction, or maintain body weight in a more healthful range. This information potentially can help to control the epidemic of obesity in the developed nations or decrease the approximately 393,000 smoking-related deaths which occur annually in the U.S.
Providing Better Health for People with Cystic Fibrosis
Patients with cystic fibrosis — an inherited chronic disease — or patients that are artificially ventilated have an increased risk of lung infection with antibiotic resistant bacteria. UVM researchers are investigating new ways to combat this bacterium.
How are they doing this?
Because the bacteria Pseudomonas aeruginosa, Klebsiella pneumoniae, and Stenotrophomonas maltophilia are often difficult to treat with conventional antibiotic therapy, UVM researchers in Microbiology and Molecular Genetics are investigating the way these bacteria adapt to the lung to identify novel therapeutic targets.
Why are animals important?
Most people with cystic fibrosis die due to bacterially-driven respiratory failure, while ventilated patients have prolonged hospital stays and increased risk of death due to bacterial pneumonia. Bacteria growing in the lung of a living animal or person have behaviors and physiologies that are much different than those growing in a petri dish. Examination of the infection process in vivo (in a living animal system) is necessary to effectively identify new therapeutic targets.
What are the significant outcomes of this research?
Cystic fibrosis is one of our most prevalent debilitating genetic diseases. About 30,000 people in the U.S. are affected by cystic fibrosis. The average life span of a person with cystic fibrosis is about 37 years, which has increased dramatically in the past three decades due to research and improvements in therapy. Ventilator-associated pneumonia represents a large healthcare burden with estimates of 60-70,000 cases of pneumonia per year caused by the bacterial species studied here. In both contexts, emergence of antibiotic resistant bacteria means that we need new ways to treat these infections.
Providing New Hope for People with Anxiety Disorders
Anxiety used to be understood only as a product of fear, within the limited context of negative emotions. Now, a cross-disciplinary team of UVM researchers — spanning the departments of Neurobiology, Psychology and Chemistry — is investigating a key region of the brain and their work holds great promise for people affected by anxiety disorders.
How are they doing this?
The research team is using rats to understand the impact of a sometimes-neurotransmitter called pituitary adenylate cyclase-activating peptide, or PACAP, in a little-studied region of the brain — the bed nucleus of the stria terminalis. Already the scientists have been able to block anxiety behaviors in rats through the use of a series of small organic molecules that block PACAP. Their goal: to find the first truly targeted medications for chronic anxiety diseases from anorexia to post-traumatic stress disorder.
Why are animals important?
Anxiety expresses itself in a wide range of behaviors. The complexity of the neurologic systems controlling these behaviors is not yet understood well enough to model anxiety in a non-living system, such as a computer. Although some research on anxiety actually uses human subjects, utilizing animals allows researchers to control for a host of environmental factors (such as diet, light cycle, temperature) which are not easily controlled using human patients. Even the genetic variables associated with anxiety can be better controlled in laboratory animals, which have been bred for many generations to minimize the genetic differences between individuals.
What are the significant outcomes of this research?
Anxiety disorders can be debilitating, making it difficult for sufferers to hold a job or to have a fulfilling personal life. Developing treatments which can specifically target the neurologic mediators of anxiety would allow many patients to resume happy and productive lives. In addition, understanding the role of PACAP in anxiety may help identify people who are at greater risk for developing anxiety disorders.