TNF superfamily trimerization inhibitors
A superfamily and inhibitor technology, applied in NGF/TNF-superfamily, medical preparations containing active ingredients, organic chemistry, etc., can solve the problem of limited identification of important residues, animal models with functional mutations that have not been reported, etc. question
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Embodiment 1
[0227] Example 1. Generation of a novel ENU-induced mouse model of severe osteopetrosis
[0228] The dentition (tles) phenotype was identified as a recessive symptom in which complete failure of tooth eruption was detected in N-ethyl-N-nitrosourea (EUC)-mutated G3 mice of both sexes ( Figure 8A ). The mutant mice also displayed growth retardation and lymphoid agenesis, characterized by abnormal development of the thymus, enlarged spleen, and absence of lymph nodes. Furthermore, these mice displayed early lethality, with 60% of tles / tles mice dying before 7 weeks of age ( Figure 8B ). Since failure of tooth eruption is a typical finding in osteopetrosis, we performed extensive histological analysis of tibias and femurs in 4- to 6-week-old tles / tles mice and littermate WT controls. Using von Kossa ( figure 1 A) and the use of hematoxylin / eosin ( figure 1 B) Staining of long bones shows severe osteopetrosis in mutant mice, while staining with tartrate-resistant acid phos...
Embodiment 2
[0230] Example 2.tles is a missense mutation in the Rank1 gene
[0231] The entire genome in 124 F2 animals (62 affected and 62 normal control siblings) was scanned with a panel of 71 polymorphic markers. An initial screen of 20 animals (10 affected and 10 normal siblings) established linkage to distal chromosome 14. Based on 248 meiosis pinpointing the location of the locus on the chromosome, linkage to 14qD3 at 44 cM between the single polymorphisms rs13482262 and rs30965774 was determined with a log odds score of 33, 8 and a p-value equal to 8 , 80912e -42 ( Figure 2A ).
[0232] Screening of the region of the candidate gene indicated the presence of the Rank1 gene, and sequencing of its coding region identified a single base transition from guanine to adenine within exon 5 (GenBank NM_011613.3), resulting in the presence of a single base transition at 278 Glycine (G) at the position is replaced by arginine (R) (G278R) ( Figure 2B ). G278 is located at the monomeric...
Embodiment 3
[0233] Example 3. Genetic confirmation of the G278R mutation of RANKL
[0234] In order to confirm that the G278R substitution of RANKL resulted in tles / tles (Rankl tles / tles ) developed osteosclerotic phenotype in mice, we made heterozygous Rankl tles / + Mice and heterozygous Rankl nude mice (Rankl + / - ) to generate Rankl - / tles compound heterozygous mice for gene complementation [13]. Rankl - / tles Mice (n=6) exhibited severe osteopetrosis characterized by failure of tooth eruption, high bone mass, and loss of osteoclasts, comparable to that in Rankl tles / tles and Rankl - / - Phenotypes developed in mice compared to ( Figure 3A ). These results verify that the transition from G to A is at Rankl tles / tles Loss-of-function mutations in mice that cause severe osteopetrosis.
[0235] Three-dimensional microstructural analysis using high-resolution micro-computed tomography confirmed that Rankl tles / tles Severe osteopetrosis in mice ( Figure 3B ), and was further verifie...
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