Peptide and application thereof in regulating megakaryocyte differentiation and treating platelet-related diseases

A technology of megakaryocytes and platelets, applied in the field of peptides and their application in regulating megakaryocyte differentiation and treating platelet-related diseases, can solve problems such as unclear effects

Inactive Publication Date: 2021-07-23
SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the role of AG...

Method used

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  • Peptide and application thereof in regulating megakaryocyte differentiation and treating platelet-related diseases
  • Peptide and application thereof in regulating megakaryocyte differentiation and treating platelet-related diseases
  • Peptide and application thereof in regulating megakaryocyte differentiation and treating platelet-related diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0058] Example 1 AGK deficiency causes thrombocytopenia in mice

[0059] (1) Construction of megakaryocyte / platelet-specific AGK knockout mice

[0060] In order to determine the role of AGK in the differentiation of megakaryocytes, the present invention constructed megakaryocyte / platelet-specific AGK knockout mice (AGK fl / fl pf4-cre + , AGK - / - ). Confirmed by immunoblotting method, AGK - / - AGK protein levels were significantly reduced in mouse platelets ( figure 1 A), at the same level of expression of cytoskeletal protein Actin, AGK - / - Protein levels of AGK were significantly reduced in mouse platelets.

[0061] (2) Mouse peripheral blood cell count

[0062] Platelet count results showed that AGK - / - The number of circulating platelets in mice was 619.7±31.44x10 9 individual / L, while the control group (Agk f / f ) The number of circulating platelets in mice was 890.6±27.15x10 9 / L( figure 1 B), so AGK deficiency results in AGK - / - The number of platelets was sign...

Embodiment 2

[0072] Example 2 AGK deficiency leads to hypofunction of bone marrow hematopoiesis and excessive extramedullary hematopoiesis

[0073] To determine AGK - / - The cause of mouse thrombocytopenia, the present invention adopts anti-CD42c antibody to stain its bone marrow and spleen megakaryocytes, and measures the number of megakaryocytes.

[0074] AGK - / - The number of megakaryocytes in mouse femur slices (4.168±0.1265 / mm 2 ) than AGK f / f Mouse femur slice (5.136±0.1388 / mm 2 ) is reduced by 20%. However, with AGK f / f Mouse spleen slice (0.4286±0.05719 / mm 2 ) compared to AGK - / - Mouse spleen slice (1.619±0.1537 / mm 2 ) in megakaryocytes increased 4-fold ( figure 2 A), where FM represents femur and SP represents spleen.

[0075] Secondly, AGK was detected by flow cytometry - / - Mice and AGK f / f CD41 in mouse bone marrow cells and splenocytes + CD42b + Percentage of megakaryocytes. AGK - / - mouse bone marrow CD41 + CD42b + Cell ratio is 6.102±0.2419%, AGK f / f mouse...

Embodiment 3

[0078] Example 3 AGK deficiency significantly affects megakaryocyte differentiation

[0079] The differentiation process of megakaryocytes into platelets is complex, including mitosis, polyploidy formation, maturation of the demarcation membrane system, maturation of the dense tubule system, and formation of secretory granules. After these processes, proplatelets germinate from the surface of megakaryocytes and further become mature platelets in the peripheral blood.

[0080] In order to further determine the role of AGK in megakaryocyte differentiation, the present invention from AGKf / f and AGK - / - Fetal livers were isolated from mouse embryos. After co-incubation with IL3 and TPO for 5 days, megakaryocytes were obtained by BSA gradient separation.

[0081] (1) Platelet formation (PPF) experiments showed that AGK deficient in AGK - / - The platelets produced by the megakaryocytes of the mice were higher than those of the control group AGK f / f Mice less ( figure 2 D), P<0....

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Abstract

The invention discloses a peptide and application thereof in regulating megakaryocyte differentiation and treating platelet-related diseases. The invention discloses application of AGK as a marker for preventing/relieving/treating platelet-related diseases, and the deficiency of AGK significantly damages platelet generation and further leads to thrombocytopenia; the AGK plays an important role in megakaryocyte differentiation and platelet formation by regulating and controlling JAK2/STAT3 signal pathway; the peptides 617V and 617F enhance JAK2/STAT3 signal transduction by promoting combination of the AGK and the JAK2, so that megakaryocyte differentiation is accelerated; the megakaryocyte differentiation can be inhibited by blocking the combination of the AGK and the JAK2; regulating the combination of the AGK and the JAK2 can be used to treat thrombocytopenia and thrombocythemia. The invention discloses an application of a medicament for regulating combination of AGK and JAK2 in preparation of a medicine for treating platelet-related diseases, the AGK plays an important role in megakaryocyte differentiation and thrombopoiesis, and prompts that a new strategy may be provided for treatment of thrombocytopenia or thrombocythemia through interaction of targeted AGK and JAK2.

Description

technical field [0001] The invention belongs to the field of biomedicine, relates to regulating the differentiation of megakaryocytes for the treatment of thrombocytopenia and thrombocytosis, and specifically relates to a peptide and its application in regulating the differentiation of megakaryocytes and treating platelet-related diseases. Background technique [0002] Platelets are an important part of the blood circulatory system and play an important role in thrombus formation, hemostasis, inflammation and tumor metastasis. Megakaryocytes are the progenitor cells of platelets in the hematopoietic system. The primitive megakaryocytes derived from hematopoietic stem cells undergo a series of complex biological processes, such as mitosis, polyploid formation, maturation of the megakaryocyte boundary membrane system, maturation of the dense tubule system, and formation of secretory granules, to form mature megakaryocytes. [0003] Thrombocytopenia is a serious condition that...

Claims

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Application Information

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IPC IPC(8): A61K38/08A61K38/16A61P7/00A61P7/04A61P7/02C07K7/06
CPCA61K38/08A61K38/16A61P7/00A61P7/02A61P7/04C07K7/06A61K2300/00
Inventor 刘俊岭徐艳艳姜豪杰
Owner SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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