الفهرس 
Bone Marrow FailureOnly 14 pages are availabe for public view
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Abstract
Telomeres are the non-encoding regions of DNA capping the ends of chromosomes, in association with various proteins. The DNA that forms the telomere consists of the sequence (5’-TTAGGG-3’)n, which is referred to as a ”telomeric repeat” since it is repeated in tandem over 5 to 15 kilobases (kb). In humans, each chromosome end contains approximately 1,000 to 2,000 telomeric repeats. Broken ends of chromosomes that do not have telomeres are prone to recombination, often resulting in fusion with other broken ends. The presence of telomeres prevents the ends of intact chromosomes from appearing like DNA breaks to the DNA replication machinery. Thus, telomeres function to guard chromosomes against degradation, fusion, and rearrangements during DNA replication. The telomere-associated proteins are important for maintaining telomere stability and regulating telomere length. These proteins include TRF1 and TRF2, Pot1, tankyrase, Rap1, and Ku. TRF1 is thought to regulate telomere length by preventing the elongation of telomeres once they reach a critical size. TRF2 appears to be important for stabilizing the chromosome ends by associating with the 3’ overhang and suppressing end-to-end fusions between chromosomes. Many additional proteins can bind indirectly to telomeres, often via TRF1 and TRF2, and together these proteins function to regulate telomere homeostasis. Telomerase is a large ribonucleoprotein complex comprised of the reverse transcriptase protein (hTERT) and an RNA template (hTR). Both components are essential for telomerase activity. Studies using mice and human cells have demonstrated that removal or downregulation of the RNA subunit leads to loss of telomerase activity, telomere attrition, and inhibition of cell growth. Furthermore, in a rare autosomal dominant form of the disease dyskeratosis congenita, the disorder is caused by mutations in the hTR which is also implicated in a subset of patients with aplastic anemia (AA). hTERT, the catalytic subunit of the telomerase holoenzyme, is a polypeptide of 1,132 amino acid residues. Ectopic expression of hTERT extends the replicative lifespan of human fibroblasts, retinal pigment epithelial cells, and endothelial cells without altering their karyotype, differentiation characteristics, or activation of known oncogenes. It is therefore thought that expression of hTERT is the rate-limiting step in telomerase activity. Studies by many groups have now demonstrated that hTERT plays a fundamental role in telomere preservation and cell proliferation. Methods of telomere length measurement include: southern blot, hybridization protection assay, flow cytometry, primed in situ, quantitative PCR and single telomere length analysis. Telomeres are important cellular structures whose integrity is essential for maintaining cell viability. There is now clear evidence that links telomeres and their associated proteins to cancer, cardiovascular disease, and ageing. Therefore, understanding the function of this biological system is attracting much attention, in an effort to use the information as a means to combat cancer and age-related diseases.Leonard Hayflick identified the importance of telomeres in maintaining cellular viability in 1961. He noted that cultured human and mammalian cells stopped dividing after roughly 50 cell divisions, which prevented the telomeres from subsequently becoming too short to protect the genome. As a self-preservation mechanism, in order to avoid genomic instability and protect the organism from catastrophic diseases, such as cancer and cardiovascular disease, cells shut themselves down by entering a state of replicative senescence the hallmark of ageing. Telomere shortening leads to cellular ageing, a process that can theoretically be reversed by restoration of telomeric structures. Telomerase, the enzyme that replicates telomeres, is therefore an ideal target for the identification and development of activators that could facilitate cell proliferation and tissue renewal. In a landmark study, in 1987 and co-workers report a key finding in the search for ways to activate telomerase. They showed that adopting a healthy lifestyle in a group of thirty patients aged 49 to 80 years increased the concentrations of telomerase in peripheral-blood mononuclear cells (PBMCs), an important result because the enzyme is not usually expressed in adult somatic cells. Specifically, the group noted that a healthy diet, exercise, and stress management led to reductions in psychological distress and low-density lipoprotein cholesterol, resulting in a significant (30%) increase in telomerase activity in the patients’ PBMCs. Several studies have shown that overproduction of psychological stress-related hormones, such as catecholamines and cortisol, causes oxidative cell damage, which can compromise telomere maintenance and replication systems.