CN-122005809-A - Application of target histone H4K77 acetylation modified substance in preparation of drugs for delaying immune senescence, modified stem progenitor cells and application thereof

Abstract

The invention provides application of a target histone H4K77 acetylation modified substance in preparation of a medicament for delaying immune senescence, a stem progenitor cell after transformation and application thereof, and belongs to the technical field of medicines. The target histone H4K77 acetylation modification or acetylation-like modification substance is a substance for increasing the level of histone H4K77 acetylation modification or acetylation-like modification level in hematopoietic stem cells and/or hematopoietic progenitor cells. The invention discovers for the first time that the increase of histone H4K77 acetylation modification or acetylation-like modification can effectively delay immune senescence and systemic senescence caused by immune senescence, and treat immune senescence and systemic senescence-related diseases caused by immune senescence. The invention provides a new choice for clinically delaying the systemic aging caused by the immune aging and treating the systemic aging related diseases caused by the immune aging and the immune aging, and has wide application prospect.

Inventors

• ZHANG HUIYUAN
• HU HONGBO
• ZHAN HUIWEN
• WEI NI
• LIU MIN

Assignees

• 四川大学华西医院

Dates

Publication Date

20260512

Application Date

20260413

Priority Date

20250425

Claims (9)

1. 1. The application of a target histone H4K77 acetylation modified or acetylation-like modified substance in preparing a medicament for delaying immune senescence or preventing and/or treating systemic senescence-associated diseases caused by immune senescence is characterized in that the substance is a substance for increasing the acetylation modification level or the acetylation-like modification level of histone H4K77 in stem progenitor cells.
2. 2. The use according to claim 1, wherein the substance for increasing the level of histone H4K77 acetylation modification in the stem progenitor cells comprises exogenously acetylation-modified histone H4K77, histone H4K77 acetylation-modification accelerator, a gene editing reagent for controlling H4K77 acetylation, and stem progenitor cells comprising stem progenitor cells containing a gene editing reagent for controlling H4K77 acetylation or exogenously acetylation-modified histone H4K77, a histone H4K77 acetylation-modification accelerator-treated stem progenitor cells.
3. 3. The use according to claim 1, wherein the substance which increases the level of acetylation modification of the histone H4K77 class in the stem progenitor cells comprises an acetylated histone H4K77 analogue, a gene editing reagent which controls the mutation of histone H4K77 into an acetylated histone H4K77 analogue, and a stem progenitor cell comprising a gene editing reagent comprising an acetylated histone H4K77 analogue, a gene editing reagent which controls the mutation of histone H4K77 into an acetylated histone H4K77 analogue.
4. 4. The method according to claim 2, wherein the histone H4K77 acetylation modification accelerator comprises a small molecule compound represented by the following structural formula II: II (II) Wherein R 1 is selected from hydrogen, C 1~6 alkyl, halogen; R 2 is selected from hydrogen, C 1~6 alkyl, halogen; The linking chain B is selected from a mixed chain comprising a C 1~10 alkylene group or a heterocyclic group.
5. 5. The method of claim 4, wherein the small molecule compound is RGFP966.
6. 6. The method of claim 3, wherein the acetylated histone H4K77 analogue is a mutant of histone H4K77 lysine mutated to glutamine or other negatively charged amino acids.
7. 7. The method according to claim 1 to 6, wherein the agent is an agent for promoting differentiation of stem progenitor cell lines or reducing differentiation of stem progenitor cell lines.
8. 8. The stem progenitor cell after modification is characterized in that the stem progenitor cell is stem progenitor cell with the acetylation or the acetylation-like degree of histone H4K77 being up-regulated, and comprises a histone H4K77 acetylation modification accelerator or an acetylated histone H4K77 analogue.
9. 9. The stem progenitor cell according to claim 8, wherein the histone H4K77 acetylation modification accelerator comprises a small molecule compound represented by the structural formula II: II (II) Wherein R 1 is selected from hydrogen, C 1~6 alkyl, halogen; R 2 is selected from hydrogen, C 1~6 alkyl, halogen; the linking chain B is selected from a mixed chain comprising a C 1~10 alkylene group or a heterocyclic group; alternatively, the acetylated histone H4K77 analogue is a mutant of histone H4K77 lysine mutated to glutamine.

Description

Application of target histone H4K77 acetylation modified substance in preparation of drugs for delaying immune senescence, modified stem progenitor cells and application thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to application of a target histone H4K77 acetylation modified substance in preparation of a medicine for delaying immune senescence, a stem progenitor cell after transformation and application thereof. Background Hematopoietic STEM CELLS (HSCs) are the source of blood cells responsible for the production of all types of blood cells, including erythrocytes, leukocytes and platelets. In the immune system, HSCs are critical, in that they not only provide a sustained supply of immune cells to the body, but also help maintain blood circulation and immune defenses. However, HSCs gradually deteriorate in function with age, especially in a long-term inflammatory environment, and have a reduced regenerative capacity, accelerating the decline of the immune system. The health and aging of the organism are closely related to the function of the immune system, and more than 80% of diseases are related to immune disorder. Systemic aging refers to the process by which the functions of multiple systems of an organism (e.g., nervous system, immune system, endocrine system, etc.) gradually decline with age. Studies have shown that with age, HSCs have significantly increased myeloid bias (myeoid bias), resulting in increased numbers of neutrophils and platelets, and decreased lymphocyte (e.g., T cells and B cells) production. This unbalanced blood composition reflects a decline in immune system function, especially in the context of chronic inflammation. Long-term low-grade inflammation not only accelerates HSCs senescence, but also promotes their excessive differentiation into myeloid cells. Myeloid lineage cells (e.g., neutrophils and monocytes) are significantly increased during immune aging. Overactivation and differentiation of myeloid lineage cells results in excessive secretion of inflammatory factors, further exacerbating chronic inflammation. For example, sema 4A-deficient mice exhibit excessive expansion of myeloid cells during aging, resulting in exacerbation of chronic inflammation. In addition, myeloid-biased hematopoietic stem cells (my-HSCs) increase in proportion during the elderly, resulting in reduced lymphohematopoietic and increased myeloid hematopoietic. At the same time, the ability of the lymphoid lineage to differentiate decreases, resulting in a decrease in the number of T cells and B cells. Lymphopenia means a decrease in the long-term defenses of the immune system, leading to a greater susceptibility to repeated infection by viruses, bacteria, and even a decrease in anticancer ability. For example, HSC clones from early aging group mice tended to differentiate into the myeloid lineage, while HSC clones from late aging group mice tended to differentiate into the lymphoid lineage. Therefore, the differentiation of the marrow system and the lymphatic system is regulated and controlled in the immune aging process, and the method has important significance for treating chronic inflammation and immune function decline. H4K77 is Lysine (Lysine) residue at position 77 on histone H4, which may undergo a variety of post-translational modifications including acetylation (acetylation), succinylation (succinylation) and ubiquitination (ubiquitination). These modifications have important regulatory roles on chromatin structure and function, thereby affecting biological processes such as gene expression, DNA replication, repair, etc. Wherein H4K77ac refers to the acetylation modification of lysine residue 77 of histone H4, and studies show that the level of H4K77ac in hepatocellular carcinoma is up-regulated, which is obviously related to the bad prognosis of patients. However, there is no report on the related immune aging of H4K77ac in the literature. Disclosure of Invention The invention aims at the application of a target histone H4K77 acetylation modified or acetylation-like modified substance in preparing medicines for delaying immune senescence or preventing and/or treating systemic senescence-associated diseases caused by immune senescence. The invention firstly provides application of a target histone H4K77 acetylation modified or acetylation-like modified substance in preparing a medicament for delaying immune senescence or preventing and/or treating systemic senescence-associated diseases caused by immune senescence, wherein the substance is a substance for increasing the acetylation modification level or the acetylation-like modification level of histone H4K77 in stem progenitor cells. Wherein the substances for increasing the acetylation modification level of the histone H4K77 in the stem progenitor cells comprise exogenous acetylation modified histone H4K77, a histone H4K77 acetylation modification promoter, a gene editing reag