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Corr.member of RAMS
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Head
of the Department (812) 234 5606, (812) 234 3356 In 1960s two scientific units were organized
in the Institute. Those were a Laboratory of biochemical genetics
headed by a Corresponding member of the USSR Academy of Medical
Sciences S. A. Neifakh and a Department of embryology headed by
professor A. P. Dyban. The Department consists of four laboratories:
The main line of investigations at the Department encircles virtually every type of human hereditary pathology i.e. from mutations in a single gene (the so called monogenic mutations) to the mechanisms of chromosomal aberrations and alterations of the entire genome.
While studying the transmission of information contained in the mitochondrial genome along the maternal lineage, the researchers of the Department elaborated an approach to obtaining a genetically engineered model of human inherited diseases associated with alterations in mtDNA structure. Energy metabolism in tissues is suppressed upon accumulation of mutant mtDNA in cells, which is manifested as a neurodegenerative disease that infrequently causes death at young age. In a series of experiments carried out in
1999-2005 the transgenic animals were obtained in whose cells human
mtDNA was contained along with their specific mitochondrial genome.
This approach lays ground for modeling various kinds of
"mitochondrial pathology", particularly because the foreign mtDNA is
maternally transmitted in the generations of animals. Similarly the population genetic screening aimed
at finding mutations in BRCA 1 are carried out. Mutations in this
gene are associated with frequent occurrence of breast and ovarian
cancer, hence our rapt attention is attracted to the families in
which these diseases have been observed significantly more often in
the past 2-3 generations. It is in such families that BRCA 1 with
the recognized or otherwise, previously unknown mutations is
revealed. The population of Saint-Petersburg is also screened for
mutations associated with the development of one of the variants of
the open-angle glaucoma. Some 10 years ago the researchers of the
Department launched a study of the conditions of both reversible and
irreversible denaturing of ceruloplasmin, a copper-containing
protein, whose structure and functions are altered in a number of
hereditary neurodegenerative diseases. It was found that removal of
all the six copper ions from ceruloplasmin molecule is followed by
its transition to the molten globule state. Some proteins can regain
their compact folding whereas the molten globule state is "the point
of no return" for ceruloplasmin, i.e. attempts to bring back its
nativity and functions failed. Several years back from now the researchers of
the Department discovered and then characterized a specific complex
formed by the two proteins of the acute phase of inflammation,
namely by ceruloplasmin and lactoferrin. Under normal conditions
lactoferrin is present in milk, saliva, lacrimal fluid and seminal
plasma, but also in the neutrophilic secretory granules. The
interaction of the proteins is selective i.e. in the simulation
experiments these two choose each other out of many possible
partners to form a complex. This phenomenon was evidenced both in
vitro and in vivo. When ceruloplasmin loses its copper ions the
latter get bound by lactoferrin. Recently our collaborators showed
that upon forming the complex with ceruloplasmin, lactoferrin
increases the enzymatic activity of the latter. From 1990-ies the researchers of the Department collaborate intensively with their colleagues from Italy, France, Germany and Scandinavian countries that in several cases allowed verifying some of our hypotheses in practice, borrowing novel methods and training young scientists to work under conditions somewhat different from what they are accustomed to at home. Collaboration is not limited to bilateral links; some of the contacts are multilateral, like the European projects in the frames of INTAS program in which the researchers from two our labs take part. The research carried out in the Department presently is financed by the President Program and is supported by nine grants from the Russian Foundation for Fundamental Research. The plans for researches in the nearest future include speeding up the studies of differentiation mechanisms with an emphasis on embryonic stem cells, enlargement of molecular genetic screening among the population of Saint-Petersburg and entire North-West of Russia, extending the top priority experimentation with transgenic animals carrying foreign mtDNA, and transition to higher level of investigation of metalloproteins using cell cultures.
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In
the recent years the studies of hereditary traits associated with
mtDNA, but also with such peculiar features of chromosomes as
chromatin packing, the presence or absence of satellite DNA
sequences have been in progress. All these kinds of inheritance of
traits are termed as 'epigenetics'. Besides, much time is spent in
studying the synthesis and structure of proteins, the particular
interest of researches being attracted by the alterations occurring
in proteins in case of hereditary pathology. In the recent 10 years
the researchers at the Department developed the population genetic
studies with the aim to elucidate the spectrum of mutations causing
socially meaningful maladies among inhabitants of Saint Petersburg
and the North-West region as a whole. Lastly, in the very recent
period a number of our colleagues have focused their efforts on
improvement of the so called cell technologies. 
In
the past 10-12 years the population of Saint-Petersburg was screened
with the aim to reveal the known and to describe some new mutations
in the low-density lipoprotein (LDL) receptor gene. Such mutations
cause 
Methylation
of daughter copies of DNA upon its replication does not always
coincide with that pattern in the ancestral copies. This phenomenon
has been studied by the researchers of the Department for over 10
years. Their results demonstrate that sister chromatids have both
different pattern of methylation and dissimilar compactization of
chromatin. This is indicative of variations in chromatid spatial
arrangement. In a preimplantation embryo the sister chromatids
differently methylated condition the subsequent cell
differentiation.
Removal
of only four of the six copper ions from ceruloplasmin results in
the loss of its enzymatic activity, though it can regain the native
state and, having incorporated the copper ions, become again the
active enzyme. Low-angle X-ray scattering revealed that copper ions
in the native ceruloplasmin play a role of a fixing "buckle"
connecting the opposite ends of the protein chain. Loss of the
crucial metal ions allows the protein's unfolding so that the N- and
C-termini previously drawn together get moved away from each other.
They no longer interact and ceruloplasmin loses its capacity to
re-incorporate copper ions and to recover its initial conformation.
The
results obtained in the Department while studying the structure and
functions of metal-binding proteins have both theoretical and
practical implications. In particular, based on the latest data, new
approaches to the application of specialized molecular probes that
enable an evaluation of compactness of a certain protein in a number
of degenerative diseases are being elaborated.