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Human on a chip systems to investigate disease comorbidities common in the aged population

人类芯片系统研究老年人群中常见的疾病合并症

基本信息

批准号：
10402384
负责人：
James J Hickman
金额：
$ 148.4万
依托单位：
HESPEROS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402384
关键词：
Accounting Acute Address Adipose tissue Affect Age Aging Anticachexia Agent Biological Aging Biological Assay Biological Models Cachexia Cardiac Cardiomyopathies Cells Cessation of life Chronic Clinical Clinical Trials Clinical Trials Design Collaborations Community Developments Decision Making Development Diabetes Mellitus Disease Disease model Drug Combinations Drug Industry Drug Kinetics Drug toxicity Elderly Evaluation Florida Formulation Functional disorder Geriatrics Glucose Goals Government Grant Human In Vitro Insulin Legal patent Link Liver Mechanics Metabolic Diseases Microelectrodes Modality Modeling Myocardium Non-Insulin-Dependent Diabetes Mellitus Organ Organ Model Organ failure Pancreas Patients Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phase Phenotype Physiological Population Preclinical Testing Property Reproducibility Research Risk Screening procedure Serum Services Skeletal Muscle System Testing Therapeutic Therapeutic Agents Toxic effect Toxicology Type 2 diabetic Universities Validation aged aging population base biological systems body system cantilever comorbidity cooking cost disease phenotype drug candidate drug development drug efficacy drug testing in vitro testing individualized medicine member models and simulation multimodality non-alcoholic fatty liver disease normal aging novel pharmacodynamic model pre-clinical preclinical study response sarcopenia screening skills success tool treatment program trial design

项目摘要

Project Summary Both older adults and the pharmaceutical industry would benefit from the development of human-on-a-chip systems to be able to systematically investigate disease comorbidities and their response to drug candidates in the aged population at the preclinical stage due to the lack of good multimodal models of disease combinations. We will investigate diseases that are most prevalent in the aged population including non- alcoholic fatty liver disease (NAFLD), cardiomyopathy, cachexia/sarcopenia and type II diabetes. The influence of metabolic diseases, especially type II diabetes, on aged and diseased patients is well known, but little studied at the preclinical level. This proposal will build upon the expertise at Hesperos and their current collaborations with UCF and the Center for Pharmacodynamics at the University of Florida branch, located in Orlando. We will use Hesperos’ patented multi-organ functional systems to investigate multiple disease phenotypes to determine how other deficits in organs or modalities enhance or cause disease, hasten progression or limit treatment options in each organ. It is also unclear how normal aging is affected by metabolic disorders, although some correlations have been observed. Human-on-a-chip models composed of multiple organs in recirculating media will provide a controlled reproducible system to evaluate responses to drugs. In addition, by comparing acute to chronic effects, the model will enable prediction of clinical trial success using models to inform clinical disease trial design based on these preclinical studies. We will build on ongoing initiatives to expand PBPK/PD modeling and simulation platforms to geriatrics by accounting for changes in the underlying pathophysiology with age. These models may also serve as screening tools during early stages of drug development and facilitate decision-making with respect to selecting the compound with a more favorable PK and formulation properties. To construct a well-defined system, we will use a common serum free medium with functional readouts using microelectrode arrays and cantilevers that are integrated on chip that allow for noninvasive electronic and mechanical readouts for acute drug responses in Phase I and chronic drug tests in Phase II. The Phase I portion of this proposal will show that three organs can be linked together - liver, cardiac and muscle- and that their response to therapeutics can reproduce responses in clinical trials. Drug and drug combinations will then be tested in the multiplexed disease models acutely for altered efficacy and toxicity compared to healthy or non-comorbidity systems. After the quantitative milestones for Phase I have been achieved, the acute studies will be extended to chronic applications in Phase II. We will also establish a type II diabetic phenotype in the system by utilizing different concentrations of insulin and glucose in a five-organ system developed by integrating the system in Aim 1 with adipose and pancreas. The disease phenotypes introduced into the system in Phase I and the combined effect of metabolic diseases will be used to evaluate therapeutics in the system.

项目总结