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NHLBI Proteomics Center
> Human Proteome
Background Information on the Human
Proteome
and the Yale/NHLBI Proteomics Center
This NIH contract funds the establishment of the National Heart Lung, Blood,
Institute (NHLBI)/Yale Proteomics Center. This new Center, which is one of 10
nationally, will support research by 21 faculty and their staffs in 12
departments and centers at Yale University that is directed at developing new
biotechnologies to study and modulate the human proteome. Although the DNA
genome that is within the nucleus of each human cell is estimated to encode for
>30,000 proteins, only a fraction of these proteins are expressed in each cell
type and it is this differential level of protein expression which largely
accounts for the difference between, for instance, a skin cell versus a liver
cell. Within a given cell different proteins vary widely in their level of
expression - with some regulatory proteins being present in perhaps only a few
copies while other proteins (e.g. those found in muscles) may be present in as
many as millions of copies/cell. Often, diseases such as cancer result in
differences in the level of expression of certain proteins. Identifying these
changes in protein expression provides opportunities for understanding the
disease process, earlier diagnosis, and more accurate classification of the
disease which may result in physicians being able to more effectively chose the
best pharmacological treatment. It also has the possibility of providing
patients with more accurate prognoses and of developing entirely new treatments.
The human proteome refers to the whole array of proteins that are found in
widely varying amounts in different human cells and tissues. Since many of these
proteins are subject to a variety of further modifications, which often play an
important role in controlling their activities, the study of the human proteome
is an extremely challenging task.
Next to water, which accounts for about 70% of
the weight of a typical mammalian cell, proteins are the next most abundant
substance - accounting for about 18% of the weight of a mammalian cell. In
addition, proteins are also found in biological fluids such as serum. Proteins
fulfill a very wide range of functions including:
- Catalyzing chemical reactions ranging from
those involved in digesting food to replicating DNA
- Mounting an immunological response to
infection
- Allowing us to see and to move
- Transporting oxygen from our lungs to organs
and tissues throughout our bodies.
- Serving as chemical messengers to regulate
growth, development, reproductive function, and metabolism.
The unique high resolution, speed and accuracy
of mass spectrometry makes this approach well suited for studies directed at
analyzing the human (and other) proteomes. Mass spectrometers can be used for
very accurately measuring the sizes of proteins and their fragments (i.e.,
peptides) that are produced by digesting proteins with proteases. Mass
spectrometers also can be used to isolate and determine the structures of
individual peptides so that the proteins from which they are derived can be
identified and quantified.
The first major goal of the research supported
by this contract is to develop new mass spectrometric based-technologies that
can be used to identify the subtle changes in protein expression that are likely
to accompany diseases - with this contract focusing on hypertension and diseases
related to vascular biology (e.g., atherosclerosis, inflammation) and
hematopoiesis, which is the formation and development of blood cells. The second
goal is to further develop the technologies and reagents needed to modulate the
activities of proteins whose level of expression is determined to change with
the onset of disease. By inhibiting or eliminating the activities of these
proteins we hope to learn more about their role in the disease process and
perhaps also discover new approaches for treating these diseases.
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