The oncostatin M receptor (OSMR) gene encodes the OSMRβ protein subunit, which is widely expressed in the skin (in keratinocytes), liver (in hepatocytes), and various immune cells. This protein subunit forms heterodimeric complexes with the signal transduction subunit gp130 (or IL-31Rα), serving as functional receptors for two key inflammatory cytokines: oncostatin M (OSM) and interleukin-31 (IL-31), respectively. Upon binding of these cytokines to their receptors, the JAK/STAT signaling pathway is primarily activated, thereby regulating multiple critical biological processes, including inflammatory responses, immune responses, and tissue regeneration. Dysregulation of the OSMR signaling pathway is closely linked to the pathophysiological processes of various diseases. In dermatology, mutations in the OSMR gene are the direct cause of primary localized cutaneous amyloidosis (PLCA), a rare hereditary disorder ^[1]. Meanwhile, excessive activation of this pathway (particularly the IL-31 axis) acts as a core driver of pruritus and inflammation in chronic inflammatory skin diseases such as atopic dermatitis ^[2]. In oncology, OSMR-based therapies hold potential for treating various cancers, including cervical squamous cell carcinoma and lung adenocarcinoma ^[3-4]. Given its central role in inflammation-driven processes and the tumor microenvironment, the OSMR signaling pathway has emerged as a key target for drug development. The hOSMR mouse is a humanized model constructed by replacing the coding sequences of exon 2 and partial intron 2 sequence of the murine Osmr gene with the Kozak-OSMR chimeric CDS-3'UTR of mouse Osmr-WPRE-BGH pA expression cassette. This model is applicable to mechanistic research on inflammatory diseases (e.g., rheumatoid arthritis, atopic dermatitis), cancers (cervical squamous cell carcinoma, lung adenocarcinoma, pancreatic cancer), cardiovascular diseases (e.g., atherosclerosis), liver diseases (e.g., fibrosis), and hematopoietic and bone marrow-related disorders. It also supports the screening, development, and safety evaluation of OSMR-targeted drugs.

TNF-like ligand 1A (TL1A), also known as TNF superfamily member 15 (TNFSF15), is a member of the tumor necrosis factor (TNF) family encoded by the TNFSF15 gene in humans. TL1A acts as a ligand for death receptor 3 (DR3) and decoy receptor 3 (DcR3), providing a stimulatory signal for downstream pathways. It regulates the proliferation, activation, and apoptosis of effector cells, as well as cytokine and chemokine production. TL1A is expressed in various immune cells, including monocytes, macrophages, dendritic cells, and T cells, as well as in non-immune cells such as synovial fibroblasts and endothelial cells. It plays a crucial role in modulating immune responses by promoting the differentiation and survival of T cells, particularly Th17 cells involved in inflammatory processes ^[1]. TL1A enhances IL-2 responses in anti-CD3/CD28-stimulated T cells and synergizes with IL-12 and IL-18 to augment IFN-γ release in human T and NK cells, biasing T cell differentiation toward a Th1 phenotype ^[2]. Dysregulation of TL1A expression is implicated in autoimmune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), primary biliary cholangitis (PBC), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS) ^[1]. TL1A has emerged as a promising therapeutic target, with ongoing research focused on developing monoclonal antibodies and other biologics to neutralize TL1A and reduce inflammation in autoimmune disorders. Clinical trial results suggest that TL1A inhibition can be used in the treatment of various autoimmune diseases, particularly IBD ^[3-5]. The huTL1A(TNFSF15) mouse is a humanized model constructed by replacing the mouse Tnfsf15 gene in situ with the human TNFSF15 gene using gene editing technology, in which the mouse Tnfsf15 endogenous extracellular domain will be replaced with the human TNFSF15 extracellular domain. The homozygous huTL1A(TNFSF15) mice are viable and fertile, and can be used for studies on T cell differentiation and survival, immune response regulation, and pathogenesis of autoimmune diseases, as well as for TL1A-targeted drug development.

The MSTN gene, also known as myostatin or growth differentiation factor 8 (GDF8), encodes a secreted protein belonging to the transforming growth factor-beta (TGF-β) superfamily ^[1]. Primarily expressed in skeletal muscle, with minor expression in mitochondria, myocardium, and brain tissue, MSTN encodes the myostatin protein, a key negative regulator of skeletal muscle development ^[1]. Myostatin, through autocrine and paracrine signaling, inhibits muscle cell proliferation and differentiation, thereby limiting excessive skeletal muscle growth and maintaining muscle mass homeostasis ^[1-4]. Thus, MSTN plays a critical role in regulating body muscle development and maintaining normal muscle mass ^[3]. Furthermore, myostatin is implicated in adipogenesis regulation, exerting an inhibitory effect on fat cell differentiation ^[2]. Mutations in MSTN are associated with myostatin-related muscle hypertrophy, characterized by significant increases in muscle volume and strength, typically without severe medical consequences ^[5]. Consequently, inhibitors targeting myostatin are considered potential therapeutic targets for diseases such as muscular dystrophy and sarcopenia, and have shown promise in improving metabolic syndrome ^[1-5]. The huMSTN(GDF8) mouse is a humanized model constructed using gene editing technology, where the mouse Mstn genomic DNA was replaced with the human MSTN genomic DNA . The murine signal peptide was preserved. This model can be used for studying the pathological mechanisms and therapeutic approaches of muscular dystrophy, sarcopenia and metabolic syndrome, and for the development of MSTN-targeted drugs.

Inhibin βE subunit (INHBE) is a member of the transforming growth factor-β (TGF-β) superfamily, highly specifically expressed in liver cells. The precursor protein of INHBE generates the inhibin β subunit after proteolytic processing. This protein is associated with various cellular processes, including cell proliferation, apoptosis, immune response, and hormone secretion. During the development of obesity and diabetes, the expression of INHBE protein inhibits the proliferation and growth of relevant cells in the pancreas and liver. Research has found a positive correlation between INHBE expression in the liver and insulin resistance and body mass index (BMI), suggesting that INHBE may be a liver factor in altering systemic metabolic status under conditions of obesity-related insulin resistance ^[1]. The studies conducted by Alnylam Pharmaceuticals and the Regeneron Genetics Center (RGC), respectively, revealed the close relationship between INHBE and fat regulation. The research demonstrated that rare loss-of-function variants in INHBE may protect the liver from the impact of inflammation, abnormal blood lipids, and type 2 diabetes by promoting healthy fat storage. Patients carrying such mutations exhibit more normal fat distribution, significantly reduced abdominal fat, improved metabolic conditions, and a decreased risk of cardiovascular diseases and type 2 diabetes ^[2-4]. These findings suggest that INHBE is a liver-specific negative regulator of fat storage. Inhibiting the expression of INHBE genes and proteins may be a potential strategy for treating metabolic disorders related to improper fat distribution and storage. Consequently, several small nucleic acid pharmaceutical companies, including Alnylam Pharmaceuticals, Arrowhead Pharmaceuticals, and Wave Life Sciences, are currently developing RNA interference (RNAi) drugs targeting INHBE to treat conditions such as obesity ^[5-7]. RNAi drugs primarily include small interfering RNA (siRNA) and antisense oligonucleotides (ASO). siRNA targets and degrades specific mRNA, while ASO binds to the target mRNA, preventing its translation or inducing its degradation, thereby inhibiting the expression of the target gene. Considering the genetic differences between humans and animals, humanizing mouse genes can accelerate the clinical development of RNAi therapies targeting human INHBE. This strain is a mouse Inhbe gene humanized model and can be used to study therapies targeting INHBE for obesity. The homozygous huINHBE mice are viable and fertile. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on this strain and provide customized services for specific mutations to meet the experimental needs in pharmacology and other fields.

The activin A receptor type 1C (ACVR1C), also known as activin receptor-like kinase 7 (ALK7), is a crucial type I serine/threonine kinase receptor belonging to the transforming growth factor-β (TGF-β) superfamily signaling pathway. Upon binding ligands such as activin AB, activin B, and NODAL, ACVR1C initiates intracellular signaling cascades by phosphorylating downstream SMAD2 and SMAD3 transcription factors, thereby regulating diverse cellular processes including cell differentiation, proliferation, apoptosis, and metabolic homeostasis ^[1]. ACVR1C exhibits a broad expression profile across various tissues, with notable enrichment in adipose tissue, pancreas, heart, and specific brain regions, suggesting its pleiotropic roles in maintaining tissue function ^[2]. Dysregulation of ACVR1C signaling has been implicated in a range of metabolic disorders, including obesity and type 2 diabetes, as well as in the pathogenesis of certain cancers like retinoblastoma, highlighting its significance as a potential therapeutic target for these conditions ^[3]. The hALK7(ACVR1C) mouse is a humanized model constructed using gene editing technology, where the region from aa.27 in exon 2 to partial intron 2 of mouse Acvr1c was replaced with "ACVR1C chimeric CDS-WPRE-BGH pA" cassette. The murine signal peptide of Acvr1c was preserved. This model can be used for studying the pathological mechanisms and therapeutic approaches of metabolic disorders such as obesity and type 2 diabetes, and certain cancers like retinoblastoma, and for the development of ACVR1C-targeted drugs.

The Zeta-chain-associated protein kinase, encoded by the ZAP70 gene, is a member of the protein tyrosine kinase family and plays a crucial role in T cell development, activation, and lymphocyte activation. Upon stimulation of the T cell antigen receptor (TCR), the ZAP70 protein is phosphorylated on tyrosine residues and, together with Src family kinases Lck and Fyn, plays a role in the initial steps of TCR-mediated signal transduction ^[1]. ZAP70 plays a key role in T cell signal transduction and is vital for thymocyte development. Defects in the ZAP70 protein can lead to severe combined immunodeficiency (SCID), characterized by the selective absence of CD8-positive T cells. Moreover, the expression of ZAP70 in B cells is associated with developing chronic lymphocytic leukemia (CLL) ^[1-2]. SKG mice are a BALB/c background strain carrying the W163C mutation in the Zap70 gene. This mutation alters the binding of the ZAP70 protein to the CD3ζ chain based on the immunoreceptor tyrosine-based activation motif (ITAM), thereby reducing TCR signal transduction and allowing autoreactive T cells to escape negative selection in the thymus and migrate to the periphery ^[3]. Under natural conditions or upon administration of serum complement activators, mice develop chronic autoimmune arthritis mediated by Th17 cells ^[4-5]. Furthermore, studies have shown that stimulation through various methods such as β-glucan or mannan can induce the disease process of rheumatoid arthritis (RA) in SKG mice, resulting in symptoms of autoimmune diseases such as ankylosing spondylitis (AS), psoriasis-like skin inflammation, RA-associated interstitial lung disease (RA-ILD), and Crohn’s disease-like ileitis ^[6-9]. The BALB/c-Zap70*W163C (SKG) mouse (referred to as the SKG mouse) is an autoimmune disease research model constructed by Cyagen through gene editing technology to introduce the W163C mutation into the Zap70 gene of BALB/c mice. The phenotype of this model is similar to that of the classic SKG mouse ^[10]. Under SPF conditions, upon triggering innate immune activation (such as β-glucan induction), it can present a variety of autoimmune disease phenotypes. Therefore, this mouse can be used for research on autoimmune diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis-like skin inflammation, RA-associated interstitial lung disease (RA-ILD), and Crohn’s disease-like ileitis, as well as T cell signal transduction.

Ms4a3 (Membrane spanning 4-domains subfamily A member 3) is a member of the MS4A transmembrane protein family and is primarily expressed in granulocyte-monocyte progenitors (GMPs) and their downstream myeloid cells, including neutrophils, monocytes, eosinophils, and basophils. Studies have shown that Ms4a3 plays important roles in myeloid cell differentiation, hematopoietic development, and immune lineage specification, and has been widely used as a marker gene for myeloid progenitors and their descendant cells ^[1]. In recent years, Ms4a3-related lineage tracing systems have been applied in studies of the developmental origins of neutrophils and monocyte-macrophage lineages, inflammatory responses, and tissue immune microenvironments. Ms4a3-IRES-iCre mice were generated by knocking an IRES-iCre cassette into the endogenous Ms4a3 locus, enabling the expression of codon-optimized iCre recombinase under the control of endogenous Ms4a3 regulatory elements. When crossed with mice containing loxP sites, Cre-mediated recombination between loxP sites is expected to occur in Ms4a3-positive cells of the offspring.

The CD19 gene encodes a member of the immunoglobulin gene superfamily. As a key co-receptor in the B cell receptor (BCR) signaling pathway, it is crucial for B cell development, activation, and differentiation. CD19, a pan-B-cell marker exclusively expressed in the B cell lineage, remains stable throughout B cell development, from pro-B cells to mature and memory B cells. It acts as a positive regulator of BCR signal transduction by forming a B cell-specific signaling complex with CD21 (complement receptor 2), CD81 (tetraspanin), and CD225 (Leu13), which lowers the threshold for antigen-induced B cell activation ^[1]. Dysregulation of CD19 is strongly linked to autoimmune diseases such as systemic lupus erythematosus (SLE) and B cell malignancies like acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma. Mutations in this gene are associated with common variable immunodeficiency 3 (CVID3), characterized by impaired B cell differentiation and hypogammaglobulinemia. Owing to its B cell-specific expression, CD19 has become a pivotal target for immunotherapy. For example, anti-CD19 CAR-T cell therapy (e.g., Tisagenlecleucel) has shown remarkable efficacy in refractory or relapsed ALL ^[2]. Recent studies have also explored CD19-targeted bispecific antibodies (e.g., blinatumomab) to enhance tumor cell clearance ^[3]. The huCD19 mouse is a humanized model generated using gene editing technology by replacing the sequence from the ATG start codon to part of intron 4 in the endogenous murine Cd19 gene with the corresponding human CD19 gene sequence. This model is applicable for studying B cell development and function, as well as therapeutic research on autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and B cell malignancies. It is an ideal research platform for preclinical efficacy evaluation of anti-human CD19 CAR-T cell therapy, and the development of bispecific antibodies and combination therapies.

Apolipoprotein E (APOE) is a critical apolipoprotein involved in lipid transport mediated by lipoproteins. As a core component of plasma lipoproteins, APOE facilitates the transport of lipids through plasma and interstitial fluid between organs, and it plays a pivotal role in the generation, conversion, and clearance of lipoproteins. In humans, the APOE gene has three isoforms (E2, E3, E4) associated with atherosclerosis and Alzheimer’s disease (AD), with the E4 allele present in approximately 14% of the population ^[1]. The ApoE4 isoform is a major genetic risk factor for late-onset Alzheimer’s disease (AD), exacerbating neurodegeneration. ApoE4-associated damage to vascular systems in the brain could have a key role in AD pathogenesis ^[2]. Beyond AD, APOE4 is linked to cardiovascular diseases due to its influence on lipid homeostasis ^[3]. huAPOE4 mice are humanized models constructed through gene editing technology. Exons 2-4 plus partial flanking sequences of the mouse Apoe gene were replaced in situ with the Mutant human APOE gene sequence, including exons 2, 3, and 4 and some downstream sequence of 3’UTR. The p.C130R (TGC to CGC) was introduced into the mutant human APOE gene. This model can be used for research on the pathogenic mechanisms and treatment methods of cardiovascular diseases such as diet-induced hypercholesterolemia, atherosclerosis, and lipid metabolism. It can also be used to study the role of human APOE gene polymorphisms in Alzheimer's disease.