Cardiovascular Diseases

In Vitro Services for Cardiovascular and Metabolic Diseases (CMD)

Service Provided

  • Assay development and execution
  • Compound screening and profiling
  • Medicinal chemistry program support
  • Mechanism of action (MOA) studies

Target Family

  • GPCR/Receptor
  • Enzyme
  • Transporter
  • Antibody
  • Biomarker

Technology Platforms available

  • Radioactivity assays
  • Fluorescence assays
  • Luminescence assays
  • Electochemiluminescence assays

  • PCR
  • Western blot
  • Isoelectric focusing electrophoresis (IEF)
  • SPR (Biacore), ITC

In Vitro Toxicity Screening

  • Cardiotoxicity
  • hERG and other ion channel test
  • Stem cell derived cardiomyocyte test on MEA
  • Comprehensive in Vitro Proarrhythmia Assay
Comprehensive In Vitro Proarrhythmia Assay (CiPA)

In Vivo Services for Cardiovascular and Metabolic Disease (CMD)

Obesity

  • Acute food intake, chronic food intake and body weight studies, breeding or establishing diet induced obesity mice, multiple clinical readouts

Diabetes

  • oGTT (mouse/rat), ipGTT (mouse/rat), ivGTT (rat), glucosuria
  • Chronic efficacy studies in db/db and other hyperglycemic models, chronic efficacy studies for improvement of insulin sensitivity
  • DIO/STZ mice

Dyslipidemia

  • Acute lipid tolerance
  • Chronic studies to monitor triglycerides, cholesterol

Hypertension

Nephropathy

  • Proteinuria, natriuresis
  • Podocyte-induced kidney injury
  • Cisplatin-induced kidney injury

Thrombosis

  • Rat arteriovenous shunt model
  • Rat tail bleeding model

Cardiovascular Disease Animal Models

  • Myocardial infarction/reperfusion induced Heart Failure
  • Atherosclerosis
  • Pulmonary Hypertension
  • Middle Cerebral Artery Occlusion

Others

  • AV-shunt
  • Tail bleeding
  • Coagulation test(PT,APTT,TT,FIB)

  • Platelet aggregation
  • Safety pharmacology
  • Telemetry BP recording system

Metabolic Diseases

Metabolic diseases are orchestrated from multiple factors and involved in multiple organs in the body. WuXi Biology offers a variety of animal models including diabetes, obesity and dyslipidemia. These include both diet-induced and genetic disease models; each model has its own features mimicking human diseases. Thus selection of the appropriate disease model based on the mechanism of action of test agent is critical for ensuring the success of the in vivo pharmacology studies. Our seasoned leaders in the field will tailor the study design to individual client’s needs.

Core Competences

Biochemical & Cell-based Assays

  • Multiple target classes (GPCRs; enzymes; NR, transporters, etc.)
  • Metabolic related target panels
  • Biochem and cell based assays (applicable to both cell lines and primary cells)
  • Safety screening panel (cytotox; cardiotox; liver tox; genetox)
  • Radiometric assays with HTS setup
  • Matching screening and hit triage platform

Functional Phenotypic Assays

  • Glucose uptake
  • Fatty acid oxidation
  • Insulin secretion in beta cells (primary islets or cell line)
  • Lipogenesis and lipolysis
  • Insulin signaling pathway (Akt, IRS phosphorylations)
  • Multiplexing profiling with MSD panels (metabolic markers)

Disease Models

  • Diabetes & Diabetic Complications
    • Chronic efficacy studies in db/db and other hyperglycemic models, chronic efficacy studies for improvement of insulin sensitivity.
    • Spontaneous Diabetes (db/db Mice, ZDF Rats)
    • High-fat Diet Induced Diabetes in Mice, Guinea Pigs and Rhesus Monkeys
    • STZ Induced Type I Diabetes in Mice and Rats
    • High-fat Diet / STZ Induced Type II Diabetes in Mice and Rats
    • Diabetic Model of Aged Rhesus Monkeys
    • Retinopathy (retina vascular leakage)
    • Wound Healing
    • Neuropathic Pain
    • Nephropathy (proteinuria, natriuresis, podocyte-induced kidney injury, cisplatin-induced kidney injury)
    • Hypertension (blood pressure measurement in telemetrized rats, (Na/K) diuresis)
    • Thrombosis (rat arteriovenous shunt model, rat tail bleeding model

  • Obesity
    • Acute food intake, chronic food intake and body weight studies, breeding or establishing diet induced obesity mice, multiple clinical readouts
    • Diet Induce Obesity (DIO) in Mice & Rats
    • Spontaneous Obesity (ob/ob Mice, Aged CD-1 Mice, fa/fa Rats)
    • Foodintake Screening
  • Dyslipidemia
    • Acute lipid tolerance
    • Chronic studies to monitor triglycerides, cholesterol
  • Metabolic Syndrome
    • Spontaneous Hypertensive Rats (SHR)

Diabetes

  • Animal models: db/db mice, ZDF rats, DIO/STZ, DN, chronic kidney failure/fibrosis in mouse, rat, NHP, dog, minipig
  • Measurements:
    • ivGTT
    • ipGTT
    • oGTT
    • ITT
    • oMMTT
    • GGI
    • Clamp
    • Oral lipid tolerance test

Obesity

  • Animal model: HFD, db/db, fa/fa, DIO
  • Measurements:
    • Food/Water intake
    • Bodyweight
    • Fasting metabolic profiling
    • DEXA measurement
    • Liver fat content quantitation by MRI (EcoMRI)
    • Serum lipid level
    • Pathology
    • Biomarkers

Dyslipidemia

  • Disease models: NAFLS, NASH (HFD, HFD-CCL4) Atherosclerosis
  • Measurements:
    • Acute lipid tolerance
    • Chronic studies to monitor TG, cholesterol
    • Biomarkers
    • Histology
    • Scoring

Target validation, target engagement, PK/PD and MOA studies

  • In vivo knockdown or over expression of target genes
  • Drug exposure in peripheral vs. CNS;
  • Disruption of specific neurons/group using stereotaxic surgery
  • Peripheral vs. ICV drug delivery
  • Histology/IHC of metabolic organs (i.e. preservation of pancreatic function)
  • Conditional taste aversion
  • Gastric emptying

Study Support Technologies

  • Hyperinsulinemic Euglycemic Clamp
  • Oxymas/CLAMS Comprehensive Lab Animal Monitoring System
    • Locomotor Activity (X, Y & Z axis monitoring)
    • Feeding (Mass monitoring);
    • Urine Collection (Mass monitoring and cooling)
    • Calorimetric Assessment (Oxygen consumption and RER)
  • Body Composition Analyis by MRI Technology (Brucker MiniSpec)
  • Rodents cardiac function and hemodynamics assessment (PowerLab system, AD Instrument)
  • Positron Emission Tomoqraphy

Analytical Support

  • Clinical Chemistry
  • FACS Calibur (BD Biosciences)
  • EnVision Multilabel Plate Reader (Perkin Elmer)
  • Meso Scale Discovery (MSD SI 6000)
  • Histology Workstation

NASH Models

NASH and NAFLD

WuXi AppTec has developed and validated animal models of NASH that captures key features seen in man. Mice are first fed with high-fat diet (HFD) to induced obesity. Carbon tetrachloride is then used to induce liver damages, leading to inflammation, cell death and fibrosis.

HFD-CCL4 NASH Model

  • Fibrosis validation
  • Histopathology validation
  • Biomarkers validation
  • In vivo efficacy test for NASH and related animals models
  • Animal study design