Biology: lead from the front edge

Biology's "Hot Ten"
Cellular communication, epigenetics, Alzheimer's, stem cells,
HIV and life expectancy – that's what biologists are interested in todayNadezhda Markina, <url>

With the help of experts "Gazeta.

Ru" deals with the areas of biological research that were included in the top ten "front edge" studies (front research) selected by the Thomson Reuters media company in 2013.

These research areas have been selected based on the number of publications and citations in recent years, which indicates their relevance. At the same time, they are unequal. "Some of these trends have been really popular for decades and have already shown significant practical value, others have become fashionable only recently and it is not yet clear what the practical way out will be," commented Gazeta.En" Raul Gainetdinov, Senior Researcher in the Department of Neuroscience and Brain Technology at the Italian Institute of Technology (Genoa) and adjunct associate professor at Duke University (USA).

1. Beta-2-adrenergic receptors coupled with human G-proteins / Human beta(2) adrenergic G-protein-coupled receptors (GPCRs)In 2012, American scientists Robert Lefkowitz and Brian Kobilka won the Nobel Prize in Chemistry for their studies of G-protein coupled receptors (GPCR).

This is a large family of transmembrane receptors, the protein spiral of which bends like a snake and sevenfold crosses the cell membrane. Hence their other names – semispiral receptors or serpentines. These receptors are ubiquitous – they bind to a large number of very diverse molecules. GPCRs transmit signals from the intercellular space into the cell.

Activation of GPCRs via their associated G-proteins (signaling intermediary proteins) triggers cascades of the most important biochemical reactions in the cell. These are the most important participants in intercellular communications, they ensure the functioning of the sensory organs – vision, smell, taste – and the response to hormones and neurotransmitters, and also serve as a target for the action of drugs and therefore are of great interest to pharmacologists.

Lefkowitz began studying these proteins in 1970, and in 1984, Kobilka came to his laboratory at Duke University in Durham and soon cloned the beta-2-adrenoreceptor gene. He later managed to study in detail the structure of the beta-2-adrenergic receptor by X-ray crystallography and describe its work. Then it turned out that other GPCRs, of which about 1000 are already known, work according to the same model.

"GPCRs are a very popular target for pharmacologists, and up to 40% of all existing medicines today act through these receptors to one degree or another," he told the newspaper.Ru" Raul Gainetdinov.

2. DNA methylation and "missing heredity" / DNA methylation analysis and missing heredityMethylation is a chemical modification of a DNA molecule that is not associated with a change in the sequence of nucleotides.

Methyl groups of CH3 are "hung" on the DNA molecule, joining cytosine (one of the four nucleotides). Like other processes that do not affect the content of hereditary information, DNA methylation is attributed to epigenetic processes (that is, occurring around the genome). However, these processes play an important role in gene expression: methylation is the most important mechanism of gene regulation, it can block the work of a gene if it is not needed at a given time in a given cell.

Epigenetic changes persist with several cell divisions, and during the formation of germ cells (meiosis) can be transmitted to the next generations. At the same time, it is not changes in the structure of genes that are inherited, but changes in gene expression. Thus, epigenetics provides the possibility of non-genomic inheritance, which is the subject of active study.

For example, it has been shown that type II diabetes, which develops in men due to malnutrition and obesity, can affect their germ cells and ultimately increases the risk of developing diabetes in their offspring. And this is not "inheritance of acquired traits" according to Lamarck, but epigenetics.

The same epigenetics explains another phenomenon. It turns out that the living conditions in childhood are remembered at the DNA level, as the methylation profile changes and, consequently, the expression level of different genes. Especially large differences were observed when comparing people with "very difficult" and "very prosperous" childhood.

As explained to the "Newspaper.En" Doctor of Biological Sciences, leading researcher at the Laboratory of Physiology and Genetics of Behavior of the Faculty of Biology of Moscow State University Inga Poletaeva, only epigenetics can explain the results of various experiments when some signs suddenly appear in the second generation of mice and rats, if their grandparents were exposed. For example, the grandchildren of rats who were "hooked" on morphine show an increased addiction to it, the grandchildren of other rats who were subjected to stress are particularly sensitive to the latter, etc.

"The concept of missing heritability, which can be translated as "missed heredity," is quite new," he told the newspaper.Ru" Raul Gainetdinov. – The fact is that in recent years it has become possible to conduct genome-wide association studies (GWAS) in a large number of patients in order to identify the relationship between certain mutations or polymorphisms in genes with specific diseases. Very often, these studies lead to the identification of several genetic variants, which, however, can be associated with the disease only in a small part of patients. So, it is assumed that there are some genetic mechanisms of missing heritability responsible for the manifestations of the disease in most patients. Epigenetic processes are very attractive in this regard. One of these most interesting mechanisms is DNA methylation, and a large number of recent works have been devoted to the analysis of DNA methylation in patients with various diseases."

3. Toxic oligomers of beta-amyloid protein in Alzheimer's disease / Toxicity of amyloid beta (Aß) oligomers in Alzheimer's DiseaseOf course, due to the aging of the population, the fight against Alzheimer's disease is increasingly relevant.

Initially, the cause of this type of senile dementia was considered to be the accumulation of beta-amyloid protein in the brain, which in the form of large aggregates forms insoluble plaques in neurons, from which the latter die. But recent studies have revealed more complex mechanisms of pathology. Scientists are trying to explain the fact that the disease begins to develop even before the appearance of plaques in neurons.

In recent years, the toxic effect of small beta-amyloid oligomers has been discovered. It has been shown that they damage synapses, lead to the loss of dendritic spines. The same oligomers cause phosphorylation of another participant in the pathological process – tau protein, which forms tangles that destroy contacts between neurons.

4. Differentiation and functioning of follicular CD4 T helper cells / Differentiation and function of follicular helper CD4 T cells (TFH)These cells are the most important link of the immune system.

The main task of CD4-type T-lymphocytes, or T–helpers, is to enhance the adaptive immune response. On their surface, they present antigens to other immune cells (T-killers, B-lymphocytes, monocytes, etc.). In addition, CD4 T cells secrete special protein molecules - cytokines, for example interferon-gamma.

Follicular CD4 T-helpers are aimed exclusively at helping B-lymphocytes, providing an adaptive immune response and creating immunological memory. This is the ability of the immune system to respond quickly and effectively to an antigen with which the body has had prior contact. Their differentiation and functioning is ensured by the expression of the main regulator – the transcription factor Bcl6.

5. ubiquitin complex and activation of nuclear factor kappa-B (NF-kB) / Linear ubiquitin chain assembly complex and activation of nuclear factor-kB (NF-kB)The terrible word "ubiquitin" means a low-molecular-weight protein that serves as a "black mark" for other proteins: being marked by the addition of this molecule, they are inevitably sent for disposal.

In 2004, two Israeli scientists, Aaron Chikhanover and Avraham Gershko, as well as American Irwin Rose, became Nobel laureates in chemistry for the discovery of ubiquitin-mediated protein cleavage.

I must say that the ubiquitin label is not always "black": only one of the forms of ubiquitin performs this role. But maybe the opposite is true: the same ubiquitin regulates the activity of signaling pathways in the cell and, therefore, participates in vital processes.

Scientists have found that sometimes a deadly "black mark" prolongs the body's life: the utilization of even slightly altered proteins is beneficial to it. It also turned out that the content of ubiquitin increases with fasting.

Nuclear factor NF-kB is a transcription factor that controls the expression of immune response, apoptosis, and cell cycle genes. Violation of its regulation leads to various pathologies, including inflammation and cancer cell degeneration.

6. Intestinal stem cells expressing Lgr5-receptor / Lgr5 receptor-expressing intestinal stem cellsStem cells were discovered in the inner wall of the intestine not so long ago.

"The Lgr5 receptor (Leucine-rich repeat-containing G protein-coupled receptor 5) belongs to the GPCRs family and is very interesting because it is almost exclusively expressed in stem cells, in particular those found in the intestine," explains Gazette.Ru" Raul Gainetdinov. – Thus, the Lgr5 receptor is practically a marker of stem cells and serves to identify these cells. The function of the Lgr5 receptor is not entirely clear today, but it is assumed that the activation of this receptor may have anti-cancer activity."

Oncologists have received data that this marker can also be used in the search for potentially malignant cells from which a cancerous intestinal tumor can develop. Thus, the theory is confirmed that most of the malignant tumors are formed from stem cells.

7. TET mutations, reduction of 5-hydroxymethylcytosine and malignant tumors / TET mutations, reduction of 5-hydroxymethylcytosine (5hmC), and malignancyMany malignant blood diseases, for example, leukemia, are characterized by mutations in the TET gene that reduce the activity of the enzyme 5-hydroxymethylcytosine.

Experts consider this gene as a target for anti-cancer therapy.

8. HIV-1 virus Vpu and Vpx proteins and damaging factors SAMHD1 and BST-2/Teterin / HIV-1 Vpu and Vpx proteins and restriction factors SAMHD1 and BST -2/TetherinVpu and Vpx are the envelope proteins of the HIV virus, they provide its ability to infect cells and produce new copies of the virus.

Moreover, the Vpu protein performs this function in the HIV-1 virus, and the Vpx protein in the HIV-2 virus. Teterin is produced by bone marrow stroma cells under the action of interferon; it is a limiter that prevents new copies of the virus from leaving infected cells. The virus has created a protective mechanism against teterin – this is the Vpu protein (Vpx). Obviously, research in this area is aimed at finding effective antiviral therapy.

9. Inhibition of the TOR signaling pathway increases life expectancy / Inhibition of TO R (Target Of Rapamycin) signaling, increased lifespan, and diseases of aging"The mammalian target of rapamycin (mTOR) protein is a key kinase involved in various mechanisms of intracellular transmission, and is responsible for many cell cycle processes, protein synthesis and transcription mechanisms," explains Gazette.

Ru" Raul Gainetdinov. – mTOR integrates signaling processes caused by insulin, growth factors, various amino acids and is a sensor of nutrients, oxygen and energy levels in the cell as a whole. It is assumed that these mechanisms are disrupted in old age, diabetes, obesity, Alzheimer's disease, depression and some forms of cancer. In particular, it is believed that mTOR inhibitors can increase life expectancy, and a number of pharmaceutical companies are developing new mTOR inhibitors for the treatment of Alzheimer's disease and other age-related diseases."

"TOR kinase plays an essential role in regulating cell growth and division in response to the presence of sufficient amino acids in food," he told the newspaper.En" Alexey Moskalev, Head of the Laboratory of Molecular Biology and Gerontology of the Institute of Biology of the Komi National Research Center of the Ural Branch of the Russian Academy of Sciences. – Studies on model animals have shown that the suppression of the activity of this gene can lead to a slowdown in aging. In our experiments, we were among the first to show that the TOR kinase inhibitor rapamycin prolongs the life of fruit flies. American studies led by Richard Miller revealed that the inhibition of TOR under the action of the pharmacological drug rapamycin significantly increased the maximum and average life expectancy in mice. Thus, TOR is a promising pharmacological target for combating various age-dependent pathologies."

10. Mitochondrial sirtuins and regulation of metabolism / Mitochondrial sirtuins and regulation of metabolism"The family of sirtuin proteins plays a role in the stress response of cells of all multicellular animals," comments Gazette.

Ru" Alexey Moskalev. – Sirtuins are induced by the action of oxidative stress, radiation, DNA damage. Some time ago, a large number of studies were undertaken on the effect on the life expectancy of a potential activator of sirtuin – resveratrol. However, it turned out that this compound does not change the maximum life expectancy (does not slow down aging) for either nematodes, fruit flies, or mice. Therefore, the prospects of sirtuins as pharmacological targets to counteract our aging are debatable."

Portal "Eternal youth" http://vechnayamolodost.ru06.05.2013