1:Cancer biology

Despite impressive progress during the past 30 years, cancer remains one of the most complex and challenging problems of biomedical research.  For this reason, cancer research is a key component of the Biomedical Research Training Program.  Cancer researchers at UNMC are engaged in work that addresses the root causes of cancer, as well as the means of enhancing the detection and treatment of cancer.  This research employs a wide range of animal and cellular model systems, includes both basic and translational research, and focuses heavily on the molecular basis of cancer.

Research Programs

Areas of particular strength include focus groups working on cancers of the prostate, breast, pancreas and blood. Cancer research at UNMC is recognized and supported by the National Cancer Institute.

Causes of Cancer: This area of research includes evaluation of the genetic, environmental and nutritional factors that contribute to cancer incidence as well as cancer prevention. Some research approaches utilized in this area of inquiry include:

• Functional Genomics
• DNA damage and repair
• Nutrition and cancer
• Environmental risk factors
• Cancer genetics
• Animal models of cancer

Molecular and Cellular Ramifications of Cancer: 

This research is focused on the differences in molecules and cells that help define cancer at the microscopic level. The following avenues are taken in research at the molecular level:

• Gene expression
• Signal transduction
• Structural biochemistry
• Functional Genomics

Diagnostics and Therapeutics: 

State-of-the-art technology couples with cutting-edge cancer research at UNMC to identify new ways of diagnosing and treating cancer. Several research innovations are used, including:

• Functional Genomics
•  Tumor vaccine development
• Radioimmunoconjugate therapy
•  Gene-targeted therapy
•  B-cell and T-cell mediated therapies

2:Cardiovascular biology

The research projects conducted by UNMC faculty within the area of Cardiovascular Biology encompass a wide range of investigations related to the fundamental understanding of how the heart and blood vessels function in health and in disease. Contemporary scientists examine these issues at all levels of biological activity, from the molecular and cellular, to the coordinated integration of separate organ systems that maintain homeostasis of the entire organism.Research training in Cardiovascular Biology at the University of Nebraska Medical Center is designed to optimize the ability of incoming students to address the many research problems that exist over this broad range. The interdisciplinary environment of the training program, which is fostered by the size and composition of the graduate faculty, facilitates the acquisition of modern experimental techniques and the development of the intellectual tools required for their implementation in the study of current problems in cardiovascular medicine.Research ProgramsThese programs can be categorized into four general themes that represent contemporary strategies for the understanding of cardiovascular function. There are no clear lines of demarcation between these categories. Indeed, interactions across thematic lines are routine and encouraged. Nevertheless, this organization is useful for the purpose of describing the breadth of research opportunities available. 

Cardiovascular Development: These studies focus on the fundamental mechanisms regulating cardiovascular development and related mechanisms responsible for congenital defects.

•  Regulation of heart and blood vessel development
•  Gene expression during cardiac development
•  Cellular and molecular mechanisms of congenital malformations

Cell Transport and Signaling: 

These studies examine the molecular mechanisms that regulate myocardial function at the single cell level.

• Mechanisms of control of ion channel and transporter activity
•  Regulation of cell surface receptors and associated second messenger systems
•  Viral pathogenesis of the myocardium.

Microvascular Function: 

The microcirculation is carefully regulated. These studies examine regulatory mechanisms and their dysfunction in disease.

• Regulation of microcirculatory resistance vessels
• Pathophysiological alterations in capillary permeability in the brain and kidney
• The effects of ischemia on cell and tissue function.

Neuro-humoral Control: 

These studies are concerned with the neural and hormonal control of the cardiovascular system.

• Reflex control of cardiovascular and renal function
•  Humoral regulators of blood volume and pressure
•  Stretch receptor and chemosensitive receptor endings in the cardiovascular system

3: Cell and developmental biology

One of the greatest challenges facing biomedical research is to fully understand the cellular and molecular mechanisms of the process of development. The application of the powerful tools of genetics, combined with the techniques of modern cellular and molecular biology, has led to an explosion of interest in the study of development. Although modern technology has provided the tools necessary to solve many unanswered questions, progress in the field critically depends on a solid intellectual foundation that generates new questions and provides the broadly-based background necessary for interpreting the answers to these questions in both historical and modern contexts. A major emphasis of the Cell and Developmental Biology area at UNMC is on the genes that control developmental events and interactions between developmentally important genes and their environment. Both transgenic and knockout mouse technologies are routinely used. Several physiological systems are under investigation. These include the hematopoietic and immune systems, the skeletal system, the cardiovascular system, and the nervous system.Research Programs

Stem Cells in development:

• Stem cells in the neural retina
• Bone marrow stem cell regulation
• Embryonic mesoderm stem cells
• Regulation of neural crest cell fate

Gene - environmental interactions in development: (see also "Genetics")

• Mechanism of folate-deficiency developmental defects
• Teratogenic mechanisms of craniofacial, neural tube and cardiovascular defects

Mechanisms of development:

• Function and evolution of homeobox genes
• Developmental regulation of neurotransmitter systems ("see also Neuroscience")
• Endocrine regulation of follicular development
• The role of growth factors in ovarian cells
• Cardiovascular development (see also "Cardiovascular Biology")

4:Cell signaling

In the past several years, the area of Cell Signaling has emerged as a major field in its own right. While the field of biochemistry has traditionally been focused on enzymology and structural proteins, results from recent years indicate that there is a huge number of proteins whose function is to modulate various aspects of cell signaling. These range from the literally hundreds of cell surface receptors that mediate cell-to-cell signals, to a wide array of second messenger and transducer proteins that convert activated receptors into intracellular biochemical/electrical signals. In recent years, it has become appreciated that these signals are not linear pathways emanating from individual receptors, but rather a network of interconnected signaling pathways which integrate signals from a variety of extracellular and intracellular sources. Thus a difficult, but exciting, challenge will be to determine how these various cellular signals work together to regulate the many aspects of cell function. At UNMC, investigators interested in cell signaling are focused on mechanisms that control cell proliferation (see also Cancer Biology), brain function (see also Neuroscience), stem cell fate (see also Cell and Developmental Biology), and cardiovascular diseases (see also Cardiovascular Biology).Research ProgramsReceptor mechanisms in cell-to-cell signaling:

• Growth factor receptor signal transduction pathways
• G-Protein receptor signal transduction pathways
• Ionotropic receptor signal transduction pathways
• Cytokine and chemokine signal transduction

Cell signaling and cell proliferation/differentiation:

• Regulation of cell proliferation: carcinogenesis
• Regulation of cell proliferation: atherosclerosis
• Mechanisms of cyclins
• Oncogene function
• Regulation of stem cell fate

Intracellular cell signaling mechanisms in normal function and disease:

• Kinases and phosphatases in cell signaling
• Molecular mechanisms of synaptic learning and memory
• Regulation of ion channels in diabetes
• Regulation of ion channels in congestive heart failure

5:Genetics

Molecular Genetics at UNMC is focused upon cancer genetics; genetic control of embryonic development, including development of the skeletal, neurosensory, cardiovascular and urogenital systems; genetics of complex diseases, including diabetes, dyslexia, obesity and neurodegeneration; and characterization of gene-environment interactions. The ultimate goal of genetics research at UNMC is to integrate data from functional and population-based studies with information from the numerous genome projects to understand genetic predisposition, susceptibility, environmental influences and pathogenesis of human disorders and disease.Infrastructure to support genetics research at UNMC includes: the Mouse Genome Engineering Facility for generation of knockout and transgenic animals; state-of-the art animal facilities; a Molecular Phenotyping Core for morphologic and histologic analyses and image processing; a DNA Microarray Core with full capabilities for whole genome expression profiling and bioinformatics support; and a DNA Sequencing and Genotyping Facility for high-throughput approaches and linkage analyses. Because of the interdisciplinary nature of genetics research at UNMC, unique opportunities exist for interactions between the academic departments, the Eppley Institute and the Munroe-Meyer Institute. Numerous genetics-related seminars are sponsored each year by the departments and institutes, providing students and postdoctoral fellows with knowledge of basic research, clinical practice and clinical applications.Research ProgramsGenetics of human diseases:

• Linkage analysis, chromosomal mapping, and positional cloning
• Genes involved in hearing loss, learning disabilities, hyperactivity
• Genes involved in neural tube defects
• Identification of genes that contribute to development of cancer

Developmental genetics:

• Neurosensory systems development and neurodegeneration
• Mechanisms of skeletal development
• Urogenital development and renal agenesis
• Neural crest development, and its role in birth defects
• Identification of regulatory elements that control gene expression in development
• Genome-wide transcriptional regulation of gene expression

Gene-environment interactions:

• Role of folate in preventing birth defects
• Genetic basis of teratogen susceptibility
• Teratogen mechanisms of action
• Metabolic and nutritional control of gene expression 

6:Immunology

Immunology research at the UNMC is multifaceted with interests ranging from autoimmune and inflammatory diseases, oncology, hematology, and infectious diseases to neurologic dysfunction.   Immunology has obvious significance in the biology of disease resistance, but also has important implications for developing modern therapies such as those involving organ transplants and stem cell transplantation.  The field of immunology also plays a more central role in understanding psychological-biochemical responses of the body and the role of inflammatory responses in neurodegeneration.Researchers and students with interests in immunology can keep in touch via several group meetings on immunology topics: the Immunology Interest Group, TransIn addition, there are three core facilities directly related to supporting immunology research: the Cell Analysis Facility, the Monoclonal Antibody Facility and the Molecular Diagnostic Laboratory.Research Programs:Stem cell transplantation and cytokines:

• Cytokine effects on stem cell mobilization and bone resorption / formation
• Stem cell mobilization and growth factor effects on immunologic reconstitution
• Cytokines for adjuvant activity for vaccines
• Cytokine therapy in autoimmune diseases such as diabetes

Immunology and disease:

• Vaccine therapy for cancers
• Host - tumor interactions
• Mechanism of tumor-specific antigen presentation to T cells
• Host-resistant mechanisms in infectious diseases
• Alcohol effects on innate immunity
• Acute phase proteins and their role in inflammatory processes

Neuro-immunologic interactions:

• The role of inflammation in neurodegenerative diseases
• microglial / macrophage modulation of neural activity
• psychoneural regulation of the immune system
• cytokine receptor function in the CNS

Virology:

• Enterovirus biology
• Autoimmune disease
• Virus-receptor interactions
• Viral vector technology
• Mechanisms of HIV pathology

7:Molecular biology

All aspects of modern biomedical research rely, to some extent, on experimental strategies that allow investigators to manipulate protein structure and function, determine how and which genes are turned on and off during a variety of physiologic, developmental, pathologic and oncogenic processes, and to understand the day-to-day workings of living cells. Doctoral research training in all these areas provides students skills in the manipulation and analysis of recombinant DNA and genes that are collectively termed "molecular biology." Such skills are critical for the conduct of state-of-the-art biomedical research in the twenty-first century.Research Programs

Gene Expression and Regulation: Understanding the molecular mechanisms that control gene expression is the goal of laboratories studying the control of expression of specific genes. Identification of both cis-acting (DNA sequence) elements in the promoter regions of these genes and enhancer elements that may lie outside the promoter is done by molecular dissection of gene regulatory elements in vitro. The genes that are being investigated using these approaches are important in:

• Regulation of cell growth and development
• Signaling pathways for hormones, neurotransmitters and growth factors
• Causes of birth defects
• Cancers of the breast, prostate, pancreas, head and neck
• Control of the immune system
• Viral pathogenesis

Analysis of Protein Structure/Function Relationships: 

A powerful approach to understanding the way in which individual amino acids and post-translational modifications of proteins may contribute to protein function evolved with the availability of complementary DNAs encoding specific proteins in conjunction with technology to modify, transfer and express the cDNAs in vitro. Recombinant DNA and mutagenesis strategies are being applied to studies on:

• Growth factor and hormone receptors
• Effectors of signal transduction pathways
• Tumor antigens and viral proteins
• Protein-protein interactions
• Pathways of protein folding
• Transcription factors
• Tumor suppressor genes
• Enzymes and glycoproteins
• Interactions between cells and extracellular matrix
• Effectors of apoptosis responses
• Transporters and membrane proteins

Transgenic Animal Models: The use of transgenic mice bearing "knock-out" or "knock-in" of particular genes has been a revolutionary approach to understanding the role of genes in many biological processes and disease states. State-of-the-art facilities are available for DNA microinjection, growth of mouse embryonic stem cells, and the preparation, propagation and maintenance of transgenic mice. Novel uses for transgenic mouse models are being developed for vaccine preparation and analysis of neurodegenerative diseases. In addition, UNMC investigators have availed themselves of the facilitys services to prepare knock-outs of:

• Transcription factors
• Tumor antigens such as mucins
• Growth factors and their receptors

Genomics and Bioinformatics: The completion of the human genome project is a landmark scientific advance that has led to the acquisition of huge amounts of DNA sequence data, made tractable only through computer analysis. With the right technology, it is now possible to ask fundamental questions about the genes that make up a human being that could not be approached experimentally in the past. UNMC facilities and technical support are available for:

• Molecular modeling
• Computational analysis of protein folding
• DNA microarray or "gene chip" technology

8:Neuroscience

Neuroscience represents one of the most fascinating and complex research areas. In terms of basic sciences, Neuroscience is one of the last remaining major frontiers in science. Clinically, neurodegenerative diseases represent a major frontier in that these diseases are among the most devastating and intractable of diseases.Research Programs:

Neurodevelopment and neurosignaling: A central question in Neuroscience relates to how the genome and experience interact to generate a structure as complex as the brain. Another major question is how the molecular and cellular structure of the brain underlies brain function and brain dysfunction. For example, in a variety of brain and psychiatric disorders (e.g., epilepsy, ischemia, depression, bipolar disorder, and schizophrenia), specific neurotransmitter signaling systems appear to be dysfunctional. Neuroscientists at UNMC also use a variety of genetic, electrophysiological, anatomical, molecular, and biochemical techniques to understand these questions.

• Neural crest stem cell differentiation and migration
• The role of neurotransmitters in brain development
• Developmental changes in antidepressant effectiveness
• Regulation of neural stem cells
• Developmental regulation of neurotranmitter systems in the brain
• Regulation of neurotransmitter release
• Glial cell regulation of neuronal activity
• Regulation of synaptic transmission
• Mechanisms of receptor trafficking to and from the cell surface

Neurovirology and neurodegeneration: Researchers at the Center for Neurovirology and Neurodegenerative Diseases focus on the role of the immune system in neurological diseases and in neural complications of AIDS infection. Inflammation is a major mechanism in which the brain responds to a variety of injuries. Whether it be AIDS or Alzheimers disease (AD), the neurons are not always directly destroyed. Disease can occur indirectly through glia (supportive cells of the brain) by setting off a chain of biochemical events that produce toxins and inflammation that can compromise neuronal cell signaling and ultimately destroy neurons. Overall, UNMC researchers use a wide diversity of techniques and experimental approaches to solve these questions.

• Identification of cytokines and chemokines responsible for neuronal damage
• The role of macrophages in AIDS dementia
• The role of macrophages in Parkinsons disease
• Neurotrophic activities of inflammatory products