'عامل تمايز النمو11' '(GDF11) المعروف أيضًا باسم' 'البروتين التشكلي للعظام 11' '(BMP-11) هوبروتين لدى البشر مشفر بواسطة عامل تمايز النمو11 الجين.

عامل تمايز النمو11 بمثابة السيتوكين وبنيته الجزيئية متطابقة في البشر والفئران والجرذان.The bone morphogenetic protein group is characterized by a polybasic proteolytic processing site, which is cleaved to produce a protein containing seven conserved cysteine residues.

العلاج GDF11 النظامية يحسن الأوعية الدموية في قرن آمون وقشرة الفئران القديمة مما أدى إلى توليد الأعصاب المحسنة. Also, systematic replenishment of GDF11 improved the survival and morphology of β-cells and improved glucose metabolism in both non genetic and genetic mouse models of type 2 diabetes.

يطلق علي GDF11 نمطًا تقديريًا من الثمنات الحرارية يشبه النمط الظاهري دون التأثير على مستويات الشهية أوGDF15 في الدم ، ويعيد مسار إشارات الأنسولين / IGF-1 ، ويحفز إفراز الأديبونيكتين من الأنسجة الدهنية البيضاء عن طريق العمل المباشر على الخلايا الشحمية ، أثناء إصلاح تكوين الخلايا العصبية في الدماغ المسن.

عامل تمايز النمو11 هومنظم لبيولوجيا الجلد وله تأثيرات كبيرة على إنتاج البروكولاجين الأول وحمض الهيالورونيك. ينشط عامل تمايز النمو11 أيضًا مسار الفسفرة Smad2 / ثلاثة في الخلايا البطانية للجلد ويحسن الأوعية الدموية في الجلد.

مكملات مستويات عامل تمايز النمو11 الجهازية ، والتي تنخفض عادة مع تقدم العمر ، عن طريق التعايش غير المتجانسة أوتسليم النظامية من البروتين المؤتلف ، والعكسات الوظيفية عكس والسلامة الجينية المستعادة في الخلايا الجذعية العضلات المسنين (الخلايا الساتلية). زيادة مستويات GDF11 في الفئران الذين تتراوح أعمارهم بين تحسنت أيضا الميزات الهيكلية والوظيفية العضلات وزيادة القدرة على ممارسة القوة والتحمل.

أعادت معالجة الفئران القديمة لاستعادة عامل تمايز النمو11 إلى مستويات الشباب آثار التلقيح والتضخم العكسي المرتبط بالعمر ، مما يكشف عن فرصة علاجية لشيخوخة القلب.

تم العثور على عامل تمايز النمو11 للحد من الإجهاد التأكسدي وكان قادرا على خفض مستويات AGEs ، أكسدة البروتين وأكسدة الدهون ، وإبطاء تراكم علامات النسيجية المرتبطة بالعمر. منع عامل تمايز النمو11 انخفاضًا كبيرًا في أنشطة CAT وGPX وSOD ،

تعزيز التعبير GDF11 عزز موت الخلايا المبرمج وتراجع تنظيم GDF11 تعوق موت الخلايا المبرمج في خطوط خلايا سرطان البنكرياس. تشير هذه النتائج إلى حتى GDF11 كان بمثابة مثبط الورم لسرطان البنكرياس.

في عام 2014 ، تم وصف عامل تمايز النمو11 كعامل تمديد الحياة في منشورين استنادًا إلى نتائج تجارب التعايش مع الفئران

 that were chosen as Science's scientific breakthrough of the year. Later studies questioned these findings.  Researchers disagree on the selectivity of the tests used to measure GDF11 and on the activity of GDF11 from various commercially available sources.  The full relationship of GDF11 to aging—and any possible differences in the action of GDF11 in mice, rats, and humans—is unclear and continues to be researched.

Effects on cell growth and differentiation

GDF11 belongs to the transforming growth factor beta superfamily that controls anterior-posterior patterning by regulating the expression of Hox genes. It determines Hox gene expression domains and rostrocaudal identity in the caudal spinal cord.

During mouse development, GDF11 expression begins in the tail bud and caudal neural plate region. GDF knock-out mice display skeletal defects as a result of patterning problems with anterior-posterior positioning.

In the mouse adult central nervous system, GDF11 alone can improve the cerebral vasculature and enhance neurogenesis.

This cytokine also inhibits the proliferation of olfactory receptor neuron progenitors to regulate the number of olfactory receptor neurons occurring in the olfactory epithelium, and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the retina.

Other studies in mice suggest that GDF11 is involved in mesodermal formation and neurogenesis during embryonic development. The members of this TGF-β superfamily are involved in the regulation of cell growth and differentiation not only in embryonic tissues, but adult tissues as well.

GDF11 can bind type I TGF-beta superfamily receptors ACVR1B (ALK4), TGFBR1 (ALK5) and ACVR1C (ALK7), but predominantly uses ALK4 and ALK5 for signal transduction.

GDF11 is closely related to myostatin, a negative regulator of muscle growth. Both myostatin and GDF11 are involved in the regulation of cardiomyocyte proliferation.

GDF11 is a regulator of kidney organogenesis, pancreatic development, the rostro-caudal patterning in the development of spinal cords, and of chondrogenesis.

Due to the similarities between myostatin and GDF11, the actions of GDF11 are likely regulated by WFIKKN2, a large extracellular multidomain protein consisting of follistatin, immunoglobulin, protease inhibitor, and NTR domains. WFIKKN2 has a high affinity for GDF11, and previously has been found to inhibit the biological activities of myostatin.

Effect on cardiac and skeletal muscle aging

GDF11 has been identified as a blood circulating factor that has the ability to reverse age-related cardiac hypertrophy in mice. GDF11 gene expression and protein abundance decreases with age, and it shows differential abundance between young and old mice in parabiosis procedures, causing youthful regeneration of cardiomyocytes, a reduction in the brain natriuretic peptide (BNP) and in the atrial natriuretic peptide (ANP). GDF11 also causes an increase in expression of SERCA-2, an enzyme necessary for relaxation during diastolic functions. GDF11 activates the TGF-β pathway in cardiomyocytes derived from pluripotent hematopoietic stem cells and suppresses the phosphorylation of Forkhead (FOX proteins) transcription factors. These effects suggest an "anti-hypertrophic effect", aiding in the reversal process of age-related hypertrophy, on the cardiomyocytes. In 2014, peripheral supplementation of GDF11 protein (in mice) was shown to ameliorate the age-related dysfunction of skeletal muscle by rescuing the function of aged muscle stem cells. In humans, older males who had been chronically active over their lives show higher concentrations of GDF11 than inactive older men, and the concentration of circulating GDF11 correlated with leg power output when cycling. These results have led to claims that GDF11 may be an anti-aging rejuvenation factor.

These previous findings have been disputed since another publication has demonstrated the contrary, concluding that GDF11 increases with age and has deleterious effects on skeletal muscle regeneration, being a pro-aging factor, with very high levels in some aged individuals. However, in October 2015, a Harvard study showed these contrary results to be the result of a flawed assay that was detecting immunoglobulin and not GDF11. The Harvard study claimed GDF11 does in fact reverse age-related cardiac hypertrophy. However the Harvard study both ignored the GDF11-specific assay that was developed, establishing that GDF11 in mice is undetectable, and that the factor measured was in fact myostatin. Also, the Harvard study combined the measure of GDF11 and GDF8 (myostatin), using a non-specific antibody, further confusing matters.

In 2016 conflicting reviews from different research teams were published concerning the effects of GDF11 on skeletal and cardiac muscle. One of the reviews reported an anti-hypertrophic effect in aging mice, but the other team denied that cardiac hypertrophy occurs in old mice, asserting that GDF11 causes muscle wasting. Both teams agreed that whether GDF11 increases or decreases with age had not been established. A 2017 study found that super-physiological levels of GDF11 induced muscle wasting in the skeletal muscle of mice.

References

Further reading

External links

• نطقب:UCSC genome browser
• نطقب:UCSC gene details

نطقب:TGF beta signaling نطقب:TGFβ receptor superfamily modulators

التصنيف: الجينات والبروتينات التطورية التصنيف: نطاق TGFβ التصنيف: البروتينات المرتبطة بالشيخوخة