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Application of notch ligand protein in the preparation of bone marrow suppression drugs for the treatment of tumor chemotherapy and early prognosis judgment

A bone marrow suppression and prognosis judgment technology, applied in the field of biomedicine, can solve the problems of insufficient research on remodeling, failure to provide, lack of Notch signaling activators, etc.

Inactive Publication Date: 2021-08-06
陈娟娟
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these sporadic reports failed to provide an effective solution to hematopoietic instability, especially chemotherapy-induced hematopoietic instability. As a classic signal of developmental regulation, Notch signaling is involved in various tissue cells including hematopoietic, vascular, and neural stem cells. Play a key regulatory role in differentiation and development
Previous studies on the regulation of hematopoiesis by Notch signaling mostly focused on the embryonic development and in vitro expansion of hematopoietic stem cells. There is no research on the regulation of Notch signaling on HSCs and sinusoidal endothelial cells in the reconstruction of chemotherapy hematopoietic injury and related mechanisms, which limits the potential of drugs. Therefore, it is urgent to explore the possibility of interfering with hematopoietic instability through Notch, so as to provide new ideas and new targets for treatment.
[0009] The current difficulties are: ① Lack of systematic in vivo studies: Notch signaling pathway plays an important role in hematopoietic development and HSC expansion, and the evidence mainly comes from in vitro experiments
②Lack of direct evidence: Notch signaling is involved in the maintenance of hematopoietic homeostasis, but there is insufficient research on the remodeling of hematopoietic homeostasis in adults
③ Lack of effective Notch signaling activators: The existing international Notch recombinant ligand proteins cannot effectively mediate the endocytosis of the extracellular segment of Notch receptors

Method used

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  • Application of notch ligand protein in the preparation of bone marrow suppression drugs for the treatment of tumor chemotherapy and early prognosis judgment
  • Application of notch ligand protein in the preparation of bone marrow suppression drugs for the treatment of tumor chemotherapy and early prognosis judgment
  • Application of notch ligand protein in the preparation of bone marrow suppression drugs for the treatment of tumor chemotherapy and early prognosis judgment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 Research experiment on the expression of molecules related to Notch signaling pathway in hematopoietic stem cells by chemotherapy

[0055] (1) Expression analysis of molecules related to Notch signaling pathway in hematopoietic stem cells of chemotherapy mice

[0056] ①Establishment of mouse chemotherapy bone marrow suppression model: 8-week-old C57BL / 6 wild male mice were taken intraperitoneally injected with cyclophosphamide, fluorouracil, cisplatin and other chemotherapy drugs to establish a variety of chemotherapy bone marrow suppression models, and the control group was intraperitoneally injected with the same amount of saline. On the 3rd, 5th, 7th, and 9th day after chemotherapy, 10 μL of peripheral blood was collected from the tail vein, and the blood routine analyzer was used to detect the number of white blood cells, hemoglobin, and platelets. If the bone marrow suppression reached (including) degree II or above, the modeling was successful. ② Expres...

Embodiment 2

[0059] Example 2 Research experiment on the effect of bone marrow hematopoietic cell deletion of classic Notch signal on hematopoiesis in chemotherapy-induced myelosuppressed mice

[0060] (1) Mating and identification of double transgenic mice

[0061] ① Mating: MxCre transgenic mice were mated with RBP-J flox / + Transgenic mice were mated to obtain heterozygous control mice MxCre; RBP-J flox / + and homozygous knockout mouse MxCre; RBP-J flox / flox . ② Identification: Take 3-week-old mice and cut off 1 cm of their tails, place them in the digestive solution containing proteinase K at 55°C for overnight digestion, obtain mouse genomic DNA according to the conventional phenol-chloroform extraction method, and use ordinary PCR methods to carry out genetic analysis. Type identification, the required primers and PCR amplification conditions have been determined.

[0062] (2) Gene knockout of RBP-J induced in bone marrow hematopoietic cells

[0063] ① Elimination: 4-5 weeks old M...

Embodiment 3

[0069] Example 3 Research experiment of Notch signaling pathway regulating the dialogue between hematopoietic stem cells and sinusoidal endothelial cells after chemotherapy bone marrow suppression

[0070] (1) Mating and identification of double transgenic mice

[0071] ① Mating: Cdh5Cre-ERT transgenic mice were mated with Rosa-NICD flox / + Transgenic mice were mated to obtain control mice Cdh5Cre-ERT; Rosa-NICD + / + (Ctrl) and overexpression mouse Cdh5Cre-ERT; Rosa-NICD flox / + (NICD). ② Identification: Take 3-week-old mice and cut off 1 cm of their tails, and put them in the digestion solution containing proteinase K for digestion overnight at a constant temperature of 55°C. According to the conventional phenol-chloroform extraction method, the mouse genome DNA was obtained, and the genotype was identified by ordinary PCR, and the required primers and PCR amplification conditions had been determined.

[0072] (2) Induction of gene activation of ICN1 in endothelial cells

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Abstract

The invention discloses the application of Notch ligand protein in the preparation of drugs for the treatment of myelosuppression caused by chemotherapy and early prognosis judgment, especially in the preparation of hematopoietic stem cells, myeloid precursor cells and bone marrow sinus endothelium after chemotherapy-induced myelosuppression Proliferation of cells and / or application of drugs to improve the hematopoietic microenvironment after chemotherapy-induced myelosuppression. The present invention answers the effect of Notch signaling on hematopoietic stem cells, myeloid progenitor cells and sinusoidal endothelium in chemotherapy bone marrow suppressed hematopoietic reconstruction from the overall human and animal, cellular and molecular levels by using a variety of genetically modified mice and improved Notch ligand proteins. The regulatory role and mechanism of cell function and remodeling, establishing the possibility of Notch signaling pathway intervening in the hematopoietic reconstruction after bone marrow instability through the hematopoietic microenvironment, providing new ideas and new targets for early prognosis judgment and treatment of myelosuppressed patients after chemotherapy and new solutions.

Description

technical field [0001] The present invention relates to the technical field of biomedicine, and the present invention also relates to the prognosis judgment and treatment of hematopoietic reconstruction after chemotherapy of malignant tumors, specifically, the application of a Notch ligand protein in the preparation of drugs for the treatment of myelosuppression caused by tumor chemotherapy and early prognosis judgment . Background technique [0002] The World Health Organization (WHO) mentioned in the "Global Cancer Report" that the number of new cancer cases in China ranks first in the world. It is undeniable that traditional chemotherapy still plays a very important role in the treatment system of cancer patients. Sequential chemotherapy has significantly improved the event-free survival rate and overall survival rate of patients with malignant tumors, especially for leukemia, lymphoma, and reproductive system tumors that can be cured by chemotherapy. Wait. [0003] Stu...

Claims

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Application Information

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IPC IPC(8): A61K38/17A61P7/00
CPCA61K38/1709
Inventor 陈娟娟周思朗夏鸳鸯龚峻梅
Owner 陈娟娟
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