The Glucagon-like peptide 1 receptor (GLP1R) gene encodes a protein that belongs to the glucagon receptor subfamily of the G protein-coupled receptor B cluster ^[1]. This cell surface receptor protein is widely expressed in tissues such as the brain, small intestine, heart, and lungs, and plays a crucial role in insulin secretion signaling cascades by responding to GLP-1 and GLP-1 analogs. Animal model data also suggest that it has neuroprotective effects. Polymorphisms of this gene are closely associated with diabetes, making the GLP-1R protein an important drug target for the treatment of type 2 diabetes and stroke ^[2-3]. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are novel anti-diabetic drugs that activate GLP-1R to enhance insulin secretion, inhibit glucagon secretion, delay gastric emptying, and reduce food intake through central appetite suppression, thereby achieving blood sugar reduction and weight loss ^[4]. The GIPR gene encodes a G-protein-coupled receptor for gastric inhibitory polypeptide (GIP), secreted by intestinal K cells after food intake. GIP was initially discovered in intestinal extracts to inhibit gastric acid secretion and gastrin release, but it was later found to stimulate insulin release in the presence of elevated glucose levels. GIPR activation stimulates pancreatic β-cells to secrete insulin and mediates fat deposition by increasing lipoprotein lipase activity, adipogenesis, and fatty acid and glucose uptake in adipocytes. GIPR is primarily expressed in EBV-transformed lymphocytes, the stomach, and visceral adipose tissue ^[6]. Knockout mice for this gene exhibit elevated blood glucose levels and impaired initial insulin response following oral glucose load. Mice with disrupted Gipr expression show resistance to diet-induced obesity ^[7]. A deficiency in the GIPR gene is associated with type 2 diabetes and obesity. Research suggests that one of the core strategies for the next generation of T2D drugs is the production of single-peptide agonists, targeting both GLP-1R activity and the glucose-dependent insulinotropic polypeptide receptor (GIPR). GIPR involvement enhances the weight-loss effects of GLP-1-based therapies. This approach improves glycemic control and weight loss in T2D patients, highlighting the GIPR signaling axis as a promising and effective co-target ^[8]. The B6-hGIPR/hGLP-1R mouse is a dual humanized model for the Gipr and Glp1r genes. Using gene-editing technology, a partial coding sequence (CDS) of the human GIPR gene was inserted into the mouse Gipr gene sequence in B6-hGLP-1R mice (Catalog No.: C001421). This model expresses the functional region of the human GIPR protein while preserving the mouse signal peptide. It can be used to study the pathogenic mechanisms of metabolic diseases such as obesity and type 2 diabetes, and the development of GIPR/GLP-1R dual agonist drugs. The homozygotes are viable and fertile.

Lipoprotein A (LPA) is a type of particle similar to low-density lipoprotein (LDL) that is considered one of the risk factors for cardiovascular disease (CVD), such as atherosclerosis, coronary heart disease, stroke, etc ^[1]. LP(a) is similar in size and lipid content to LDL (low-density lipoprotein) and also contains the lipoprotein ApoB-100. However, unlike LDL, LP(a) additionally contains a variable-length lipoprotein called Apo(a), which covalently binds to ApoB-100 through a single disulfide bond. LP(a) plays an important role in systemic lipid transport, guiding inflammatory cells into blood vessel walls and leading to smooth muscle cell proliferation. Furthermore, it is involved in wound healing and tissue repair, interacting with the components of blood vessel walls and the extracellular matrix ^[2]. However, LP(a) can also cause arterial narrowing by adhering to the arterial wall, accelerating the formation of blood clots, and thereby triggering a series of pathological changes related to coronary heart disease, cardiovascular disease, atherosclerosis, thrombus formation, and stroke ^[3]. The plasma concentration of LP(a) is closely related to genetic factors and is primarily regulated by the LPA gene. Therefore, the LPA gene is an important potential target for cardiovascular disease treatment. The LPA gene encodes a serine protease that inhibits the activity of tissue-type plasminogen activator I. Fragments of this protein, generated through protein hydrolysis, can adhere to atherosclerotic lesions in arteries, promoting blood clot formation. The LPA gene is expressed in both humans and non-human primates but is not expressed in mice. Constructing mouse models expressing the human LPA gene is of significant importance for developing lipid-lowering drugs, which can drive the development of novel therapies for cardiovascular diseases. Currently, various novel therapies targeting the transcription rate of the LPA gene are under development, including small interfering RNA (siRNA) and antisense oligonucleotides (ASO) ^[4]. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a serine protease primarily produced in the liver but expressed in other tissues, including the intestine, heart, and neurons. The N-terminal domain of the PCSK9 protein is responsible for protein localization and stability, while the C-terminal domain is responsible for protein enzymatic activity ^[5]. The Low-density lipoprotein receptor (LDLR) is a receptor that is responsible for clearing low-density lipoprotein cholesterol (LDL-C) from the blood. PCSK9 cleaves the intracellular domain of LDLR on the cell surface, causing it to detach from the cell membrane and be transported to the lysosome for degradation, promoting LDLR degradation, and increasing plasma LDL-C. Overexpression or gain-of-function mutations of the PCSK9 gene can lead to LDL-C accumulation by reducing LDLR levels. This can cause hypercholesterolemia, which increases the risk of cardiovascular diseases, such as atherosclerosis and coronary heart disease, and neurodegenerative diseases, such as Alzheimer's disease ^[6]. PCSK9 has emerged as a key target for the development of lipid-lowering drugs. Several PCSK9-targeted antibodies or small nucleic acid drugs have been approved for marketing worldwide, including evolocumab from Amgen, alirocumab from Sanofi and Regeneron, and inclisiran from Novartis. These drugs primarily work by inhibiting PCSK9 activity or preventing PCSK9 protein from binding to LDLR, lowering LDL-C levels in the blood to treat hypercholesterolemia ^[7-8]. In addition, PCSK9 can promote tumor growth and development by regulating cell proliferation, migration, and invasion. It can also regulate the expression of inflammatory factors that contribute to inflammation. Therefore, targeting the expression of PCSK9 has been investigated in tumor immunotherapy and autoimmune disease therapy ^[9-10]. The B6-hLPA (CKI)/Alb-cre/hPCSK9 mouse model is generated by crossing B6-hLPA (CKI) mice (Catalog No.: C001521, a mouse strain with conditional expression of the human LPA gene), Alb-Cre mice (liver-specific Cre-expressing mice), and B6-hPCSK9 mice (Catalog No.: C001617). This model harbors two cardiovascular disease risk factors, namely Lp (a) (lipoprotein (a)) and PCSK9, making it suitable for research on hyperlipidemia, stroke, coronary heart disease, and other atherosclerotic cardiovascular diseases (ASCVD).

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a serine protease primarily produced in the liver but expressed in other tissues, including the intestine, heart, and neurons. The N-terminal domain of the PCSK9 protein is responsible for protein localization and stability, while the C-terminal domain is responsible for protein enzymatic activity ^[1]. The Low-density lipoprotein receptor (LDLR) is a receptor that is responsible for clearing low-density lipoprotein cholesterol (LDL-C) from the blood. PCSK9 cleaves the intracellular domain of LDLR on the cell surface, causing it to detach from the cell membrane and be transported to the lysosome for degradation, promoting LDLR degradation, and increasing plasma LDL-C. Overexpression or gain-of-function mutations of the PCSK9 gene can lead to LDL-C accumulation by reducing LDLR levels. This can cause hypercholesterolemia, which increases the risk of cardiovascular diseases, such as atherosclerosis and coronary heart disease, and neurodegenerative diseases, such as Alzheimer's disease ^[2]. PCSK9 has become an important target for the development of lipid-lowering drugs. Several PCSK9-targeted antibodies or small nucleic acid drugs have been approved for marketing worldwide, including evolocumab from Amgen, alirocumab from Sanofi and Regeneron, and inclisiran from Novartis. These drugs primarily work by inhibiting PCSK9 activity or preventing PCSK9 protein from binding to LDLR, lowering LDL-C levels in the blood to treat hypercholesterolemia ^[3-4]. In addition, PCSK9 can promote tumor growth and development by regulating cell proliferation, migration, and invasion. It can also regulate the expression of inflammatory factors that contribute to inflammation. Therefore, targeting the expression of PCSK9 has been investigated in tumor immunotherapy and autoimmune disease therapy ^[5-6]. Apolipoprotein E (ApoE) is a lipid particle-associated polymorphic carrier protein encoded by the APOE gene. It is a core component of plasma lipoproteins, participating in the production, transport, and clearance of lipoproteins. ApoE is associated with chylomicrons, chylomicron remnants, high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL), especially showing preferential binding to HDL ^[7]. ApoE is the most important lipid transport protein in the body, having a profound impact on lipid metabolism. The interaction of ApoE with the low-density lipoprotein receptor (LDLR) is essential for the normal processing (catabolism) of triglyceride-rich lipoproteins ^[8]. In peripheral tissues, ApoE is primarily produced by the liver and macrophages and mediates cholesterol metabolism. In the central nervous system, ApoE is produced mainly by astrocytes and is the major cholesterol carrier in the brain. ApoE is essential for transporting cholesterol from astrocytes to neurons ^[7-10]. In addition, ApoE forms a complex with activated C1q, becoming a checkpoint inhibitor target of the classical complement pathway ^[11]. Polymorphisms of the APOE are associated with Alzheimer's disease and lipid accumulation, hyperlipidemia, atherosclerosis, high cholesterolemia, etc., and are related to the risk of various cardiovascular diseases. The B6-hPCSK9/Apoe KO mice are obtained by crossing B6-hPCSK9 mice (Catalog No.: I001179) with B6J-Apoe KO mice (Catalog No.: C001507). B6J-Apoe KO mice exhibit elevated cholesterol levels and spontaneous atherosclerosis phenotypes due to the disruption of ApoE protein synthesis, further exacerbated under a high-fat diet (HFD). On the other hand, B6-hPCSK9 mice have the mouse Pcsk9 gene sequence replaced with the human PCSK9 gene sequence through gene editing technology, expressing the human PCSK9 protein. They can be used for the development of PCSK9-targeted drugs in hyperlipidemia, stroke, coronary heart disease, and other atherosclerotic cardiovascular diseases (ASCVD). The B6-hPCSK9/Apoe KO mice, while expressing the human PCSK9 protein, exhibit significantly elevated cholesterol levels and spontaneous atherosclerosis characteristics. These mice provide an ideal platform for the PCSK9-targeted drug development in hyperlipidemia and cardiovascular diseases, demonstrating good clinical and pathological relevance.

The Glucagon-like peptide 1 receptor (GLP1R) gene encodes a protein that belongs to the glucagon receptor subfamily of the G protein-coupled receptor B cluster ^[1]. This cell surface receptor protein is widely expressed in tissues such as the brain, small intestine, heart, and lungs, and plays a crucial role in insulin secretion signaling cascades by responding to GLP-1 and GLP-1 analogs. Animal model data also suggest that it has neuroprotective effects. Polymorphisms of this gene are closely associated with diabetes, making the GLP-1R protein an important drug target for the treatment of type 2 diabetes and stroke ^[2-3]. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are novel anti-diabetic drugs that activate GLP-1R to enhance insulin secretion, inhibit glucagon secretion, delay gastric emptying, and reduce food intake through central appetite suppression, thereby achieving blood sugar reduction and weight loss ^[4]. The leptin (LEP) gene, also known as the OB gene, encodes the leptin protein, which is secreted into the circulation by white adipocytes and plays a major role in regulating energy homeostasis. Circulating leptin binds to leptin receptors (LEPR) in the brain, activating downstream signaling pathways that inhibit feeding and promote energy expenditure. Leptin also has multiple endocrine functions and is involved in physiopathological processes such as immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation, and wound healing ^[6]. Mutations in the LEP gene and its regulatory regions lead to severe obesity and morbid obesity with hypogonadism in humans and are also associated with the development of type II diabetes ^[7]. The B6-hGLP-1R/ob mouse model, generated by mating B6-hGLP-1R mice (Catalog Number: C001421) with Lep KO (ob/ob) mice (Catalog Number: C001368), is a metabolic disease model. It can be used for research on the pathogenic mechanisms of various metabolic diseases, such as obesity and type II diabetes, and for screening GLP-1RA drugs.

Complement factor B (CFB) is a circulating serine protease that plays a central role in the alternative pathway of the complement system, a critical component of innate immunity. Encoded by the CFB gene, this protein is primarily synthesized by hepatocytes, adipocytes, and monocytes, reflecting its systemic and local involvement in immune surveillance and inflammation ^[1]. Upon activation by factor D, CFB forms the active enzyme factor Bb, which, in complex with complement component C3b, constitutes the alternative pathway C3 convertase (C3bBb). This convertase catalyzes the cleavage of C3 into the anaphylatoxin C3a and the opsonin C3b, leading to the amplification of the complement cascade and the subsequent elimination of pathogens and damaged cells ^[2]. Dysregulation of CFB activity, often stemming from genetic polymorphisms within the CFB locus, has been implicated in the pathogenesis of several human diseases, including age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and systemic lupus erythematosus (SLE), underscoring the delicate balance required for proper complement regulation and immune homeostasis ^[3-4]. These associations highlight CFB as a key mediator of both protective and pathological immune responses. The MASP2 gene encodes MASP-2, a serum serine protease that serves as a key mediator in complement system activation. MASP-2 initiates the lectin pathway by forming complexes with pattern recognition molecules such as mannose-binding lectin (MBL) and ficolins. Upon pathogen recognition by MBL, MASP-2 is activated and subsequently cleaves complement components C4 and C2, leading to the generation of C3 convertase and triggering downstream complement activation. Beyond its role in the complement cascade, MASP-2 also contributes to the coagulation pathway by cleaving prothrombin to generate thrombin, thereby linking innate immunity and hemostasis ^[5]. Emerging evidence highlights the clinical significance of MASP2 gene polymorphisms, which are associated with altered susceptibility to infectious diseases and immune-related disorders. Reduced plasma levels of MASP-2 have been linked to increased vulnerability to HIV infection, while elevated MASP-2 activity may exacerbate inflammatory responses ^[6]. Given its pivotal role in immune regulation, MASP-2 has emerged as a promising therapeutic target. Inhibition of MASP-2 is currently under investigation as a potential strategy for treating a range of conditions, including IgA nephropathy (IgAN) ^[7], atypical hemolytic uremic syndrome (aHUS), and transplant-associated thrombotic microangiopathy (TA-TMA) ^[8]. The B6-huCFB/hMASP2 mouse is a dual-gene humanized model obtained by mating B6-huCFB mice (catalog number: C001710) with B6-hMASP2 mice (catalog number: C001592). This model can be used for research on the pathological mechanisms and treatment methods of autoimmune diseases and infectious diseases, as well as the development of CFB/MASP2-targeted drugs.

B6-Uox KO/huURAT1 mice are humanized disease models obtained by crossing Uox KO mice (catalog No.: C001232) with B6-huURAT1 mice (catalog No.: C001704). This model can be used for studying the pathological mechanisms and treatment methods of uric acid metabolism-related diseases such as hyperuricemia and gout, as well as for screening and developing URAT1-targeted therapies and evaluating preclinical efficacy and safety. It is worth noting that heterozygous Uox KO mice can survive and are fertile, while homozygous Uox KO mice need to be maintained with drugs such as Allopurinol after birth.

The B6-Uox KO/huXDH mice are humanized disease models obtained by mating Uox KO mice (catalog No.: C001232) with B6-huXDH mice (catalog No.: C001586). This model is suitable for studying the pathological mechanisms of hyperuricemia and gout, and provides an ideal preclinical research platform for the development of novel xanthine oxidase inhibitors and small nucleic acid therapies. It is worth noting that heterozygous Uox KO mice can survive and are fertile, while homozygous Uox KO mice require drugs such as Allopurinol to maintain their survival after birth.