Proteomics
Proteomics is the comprehensive study of the proteome, which encompasses all proteins expressed from genes at any given time in a specific cell, tissue, or organism. The field recognizes that proteomes vary widely among different organisms and can dynamically change in response to factors such as aging, diet, exercise, medications, and diseases. To better understand and analyze proteomes, researchers approach the study through three primary methodologies: functional proteomics, which focuses on identifying and quantifying proteins; structural proteomics, which aims to determine the three-dimensional structures of proteins; and mapping protein-protein interactions to elucidate biological networks and disease mechanisms.
One of the significant applications of proteomics is in medicine, particularly in identifying disease-specific biomarkers that can lead to early diagnostics and targeted treatments. For instance, alterations in protein patterns in blood plasma can indicate the presence of diseases like cancer long before symptoms arise. Advances in technology, including high-throughput processing and mass spectrometry, have greatly enhanced the capacity to analyze large-scale proteomic data. Given the complexity of protein interactions and functions, proteomics seeks to integrate findings from various studies, fostering collaboration among researchers while contributing to a broader understanding of human health and disease. Overall, the potential of proteomics to revolutionize medical diagnostics and therapeutics makes it a critical area of ongoing research.
Proteomics
ANATOMY OR SYSTEM AFFECTED: All
DEFINITION: The study of the proteome, the collective body of proteins expressed from genes at any given point in time in any given cell, tissue, or organism. Proteomes differ for each kind of organism and are quite dynamic, changing their protein composition in response to such factors as aging, diet, exercise, medication, and disease.
Methodologies
Proteomics focuses on developing a proteome profile for any given cell, tissue, or disease through three main perspectives. Functional (quantitative) proteomics aims to identify, quantify, and localize proteins within proteomes. Structural proteomics aims to develop a precise three-dimensional structure of each protein in normal and abnormal states, which is vital to clinical diagnostics and drug discovery. Mapping protein-protein interactions aims to understand how proteins interact with one another in complexes, forming networks and pathways of biological activity to understand how diseases originate and progress.
Proteome size, complexity, and dynamics are the current biggest challenges to proteomics. For this reason, this field is closely tied to technological advances. The use of robotic techniques has led to processing hundreds of thousands of extremely small samples every day, which is called high-throughput. To profile proteomes, they must first be isolated, their proteins separated and then purified through large-scale two-dimensional polyacrylamide gel electrophoresis and/or mass spectrometry. Protein structural information is then determined using protein sequencing, mass spectrometry, and/or x-ray crystallography. Assigning protein function within a proteome involves protein and/or antibody microarray analyses to determine biochemical pathway involvement and any protein-protein interactions. Typically, laboratories will specialize in one of these approaches. All laboratories, however, must be able to integrate the information that they find with the discoveries of others. The creation of databases that hold, organize, and link the massive amounts of proteomic information generated to genomic information has been made possible only through advances in bioinformatic computer technology.
Medicine and Proteomics
Most diseases create alterations in cellular function. Complex diseases such as cancer, heart disease, and diabetes cannot be treated effectively if the underlying cause and proteins responsible remain unknown. However, the current practice of biomedical research is unable to identify these changes or determine how they relate to disease processes quickly enough to develop the needed diagnostics and treatment. Identifying proteomic components that are specific for a disease (biomarkers) is a major effort of proteomic research. The aim is to develop diagnostic kits that detect the very early phase of a disease. Within populations, the diagnosis, prognosis, treatment, origins, and progression of a disease are public health issues overseen by epidemiologists. Genetic epidemiology is an emerging discipline that is closely following proteomic progress to develop better public health policies and planning. Proteomics is also expected to identify targets for new drugs.
In the early stages of development, proteome profiling has already shown that the human cardiac proteome is reproducibly and uniquely altered for different heart diseases and disorders. Biomarkers specific to prostate and breast cancer have been identified. These first studies encouraged proteomic researchers to turn to disease proteomic profiling. Because most diseases create protein alterations in blood plasma long before symptoms appear, proteomic serum and plasma profiling is a major research effort. Researchers have identified a blood plasma proteomic profile for ovarian cancer that appears to predict the disease accurately. Other researchers have turned to the proteomic profiling of pathogens, such as antibiotic-resistant bacteria or those organisms causing malaria or stomach ulcers. The goal is to identify biomarkers for use as drug targets and for the development of diagnostic kits.
One promising application of proteomic technology is in the area of early detection of disease. Historically, the identification and examination of disease markers has been based on individual proteins, which is not always reliable. For example, the assay for prostate-specific antigen (PSA) is used to screen for prostate cancer, but levels of this antigen may also be raised in benign conditions of the prostate, and other unrelated conditions can lead to false-positive results for this screen. Thousands of small proteins can be analyzed simultaneously using proteomic microarrays, and these results may suggest patterns of disease that may be useful for early detection. The potential therefore exists to use a panel of diagnostic markers, rather than a single protein, to identify a given disease state more accurately.
Perspective and Prospects
The origins of proteomics can be traced to the technique of separating complex mixtures of proteins by two-dimensional polyacrylamide gel electrophoresis in the mid-1970s. Refinement of the technique and the addition of protein sequencing methods enabled identification of the separated proteins. In the 1990s, advances in mass spectrometry provided a highly accurate, sensitive analysis of proteins capable of handling thousands of samples.
The final impetus for proteomic research was a direct outcome of the technological advancements of the Human Genome Project, including microarray analyses, the concept of high-throughput, and a paradigm shift in biological science research. Paramount was the recognition that the protein products of a gene, not the gene itself, are responsible for cellular processes. It became clear that the function of proteins in cellular pathways and processes could not be deduced from the deoxyribonucleic acid (DNA) sequence alone. Efforts quickly turned to studying all proteins and their functions in the context of genetics and diseases. As an emerging discipline, proteomics represents a new research form that is more global and integrative than traditional protein research in the past, which concentrated on the study of single proteins.
A concern among researchers is the sequestering of data generated in proteomic research for private company use or through aggressive patenting of results. Because of the complexity of the research, it is considered necessary for all to share their data in a public forum. The Human Proteome Organization (HUPO) was created to orchestrate cooperative sharing of both private and academic research efforts. First and foremost is the recognition that research must focus on what constitutes a normal proteome before assessing disease states, including defining the range of variability in normal proteomes as a result of age, ethnicity, and physiology. HUPO considers the human serum, liver, and brain to be the most important organs for proteomic profiling in the hope that these studies will lead to new drugs, diagnostics, and a basic understanding of cellular function. In whatever form proteomics takes, it is expected to change the practice of medicine drastically.
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