Leslie Leinwand's research focuses on how cardiac and skeletal muscle adapt to stimuli, particularly the pathways involved in heart enlargement in response to exercise and disease. Using the issue of human health and disease, her HHMI project includes an interdisciplinary science course and a laboratory research program for undergraduates, a mentor training program, and a lecture series open to the public and workshops for high school teachers.
Most undergraduates at large universities do not see the connection between bench research and medicine. In addition, major research universities have the special challenge of encouraging their most prominent faculty to include undergraduates in their research laboratories. It is also critical that we have a more scientifically literate citizenry, and we need to communicate better about the positive impact that scientific research has on society.
This project strives to enhance science education by addressing these issues. At its center is the notion that people are motivated to learn about subjects that have personal relevance; human health and disease offer that relevancy for many and can be used to convey the benefits and nature of the process of scientific research and education.
One part of this project involves developing new curricula for undergraduates. Undergraduates have few opportunities to learn about the breadth of scientific research—curricula rarely involve multiple disciplines. To change that, we are offering a new interdisciplinary course open to sophomore life science majors in the College of Arts and Sciences and the College of Chemical and Biological Engineering. Enrollment will initially be 100 students per semester, thus reaching 800 students in the next four years. The course will be taught by University of Colorado scientists and physician-scientists as well as scientists from the biotechnology community. Using human disease as a focal point, the lectures will cover a broad array of topics ranging from behavioral genetics to exercise physiology to microbial communities in common disease states. The students work in groups, for example, to evaluate the direct-to-consumer DNA testing companies. They also research a current drug on the market and write a paper about it. The undergraduate laboratory research program (titled the "Python Project") will use pythons to help students understand the biology of python hearts and relate that to human heart disease. This understanding may lead to new therapeutics.
The Python Project offers each student the opportunity to participate in all aspects of experimental design, data acquisition, analysis and interpretation. In addition to serving the undergraduate population, this model also addresses a growing need for the involvement of post-doctoral fellows to implement science curriculum reform. Importantly, the project was performed in collaboration with the Leinwand laboratory with each student contributing data that relate to the sponsor lab’s ongoing research. The Leinwand laboratory examines molecular mechanisms that regulate organ hypertrophy (enlargement of an organ or tissue from the increase in cell size or number) in Burmese pythons after feeding. The rapid growth of the python organs provides a unique research opportunity for students to examine the expression of a set of candidate genes thought to be involved in cellular hypertrophy or proliferation. The course is organized into six laboratory hours and one 50-minute lecture per week. Over a four-year period, up to 16 undergraduate students were enrolled per semester. Undergraduate students majoring in MCDB in their junior or senior year were eligible to enroll in The Python Project as an elective course.
Research in the Leinwand Lab
All of the projects in the lab have a central goal of translating our findings to health and disease. We focus our efforts on cardiac and skeletal muscle biology using a wide array of molecular biological, biophysical, cellular, and animal model tools.
The Python Project: We have used molecular approaches to understand the biology of the Burmese python to promote beneficial cardiac adaptation in the setting of disease. The Burmese python is an infrequent feeder, with 6-12 months between meals. Such a meal can easily be 25 percent to 50 percent of the mass of the python. Amazingly, most of the organs in the body double in size in 24 hours and reduce back to pre-feeding size in a matter of days. The heart grows by cellular hypertrophy and becomes extremely oxidative, burning the extremely high concentrations of lipids in the blood. In many ways, the python heart has many of the characteristics of the heart of an athlete. We have identified a combination of three fatty acids in the plasma that can promote cardiac growth in pythons and in mice. We are testing whether these fatty acids can prevent or treat heart disease in mice. We also are trying to understand how the organs in the python reduce their size after such a meal.
Myosin Myopathies: There are 10 myosin motors encoded by distinct genes that are expressed in cardiac and skeletal muscle. Our goals have been to understand the functions of each of these motors and how mutations in them cause disease. Thus far, more than 300 different mutations in five of these genes have been linked to a variety of cardiac and skeletal myopathies. We are testing the functions of the mutated myosins in vitro, and then expressing them in muscle cells to understand their effects on sarcomeres. For a subset of mutants, we have made transgenic mouse models to study pathogenesis. Because these myosin myopathies are autosomal dominant, people have one wild type myosin and one mutant myosin. Therefore, we are attempting allele-specific silencing of the mutant allele in transgenic mice.
Sex differences in the heart: Heart disease is the number one killer of both men and women, but numerous studies have suggested that males and females have very different cardiac physiology and that they respond to both exercise and disease in distinct ways. For example, while younger men have more mortality due to heart disease than age-matched women, older women have more mortality than age-matched men. We are investigating sex differences in the cardiac myocyte including the roles of estrogen and its receptors. Female cells have higher activation of intracellular pro-survival signaling than male cells. One potential unfortunate consequence of this activated signaling is that females are more susceptible to chemotherapy-induced cardiotoxicity. We are investigating mechanisms to treat this cardiotoxicity. While males have lower levels of circulating estrogen than females, the hormone and its receptors are important in both sexes. In fact, estrogen receptors are expressed at the same level in male and female myocytes. We are making conditional estrogen receptor-null mice that are lacking receptors in cardiac myocytes and testing their responses to both physiologic and pathologic stimuli.
Micro RNAs in heart and skeletal muscle: We are interested in the role that miRNAs play in the plasticity of heart and skeletal muscle to a wide variety of stimuli such as exercise, pregnancy, and disease. We have carried out deep sequencing analysis of miRNAs in skeletal muscle and have focused on the miR-30 family that appear to regulate a large number of genes during skeletal muscle development and are themselves regulated in a number of disease states. We also study miR-206 that is potently upregulated in muscular dystrophy.
As of May 2014