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Small molecules for expansion of islet beta-cell mass in diabetes

用于扩张糖尿病胰岛β细胞质量的小分子

基本信息

批准号：
9902446
负责人：
CHRISTOPHER B NEWGARD
金额：
$ 67.08万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902446
关键词：
Affect Animals Apoptosis Autoimmune Process B Cell Proliferation Beta Cell Bioavailable Biological Assay Biology Blood Glucose C57BL/6 Mouse Cell Proliferation Cells Chemicals Clinical Consultations Defect Development Diabetes Mellitus Dose Drug Kinetics Ensure Exhibits Exposure to FDA approved Fatty Liver Foundations Genomics Glucose tolerance test Goals Half-Life Health Care Costs Healthcare Systems Helminths Histologic Homeobox Human Immunodeficient Mouse Injectable Injection of therapeutic agent Institutes Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Intraperitoneal Injections Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Kidney Lead Ligands Metabolic Metabolism Michigan Modality Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Oral Pathway interactions Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Population Preclinical Drug Development Rattus Reporter Resort Rodent Rodent Model S-Phase Fraction Series Serum Stimulation of Cell Proliferation Structure of beta Cell of islet Testing Therapeutic Therapeutic Intervention Therapeutic Uses Tissues Universities analog base capsule cell regeneration comorbidity cost diabetes mellitus therapy drug discovery efficacy study endoplasmic reticulum stress experience follow-up functional loss glucose tolerance glycemic control improved in vivo insulin secretion insulin sensitivity islet lead optimization lead series novel novel therapeutics promoter response scaffold side effect small molecule transcription factor type I and type II diabetes virtual screening

项目摘要

Project Abstract/Summary Diabetes currently affects 9.3% of the U.S. population totaling $245 billion annually in U.S. healthcare costs. Current therapies for diabetes are limited in their ability to control blood glucose and/or enhance insulin sensitivity. Given the magnitude of diabetes costs and complications, new therapies with reduced side effects are urgently needed. The common defect in both type 1 and type 2 diabetes is the loss of functional pancreatic islet -cell mass. A therapeutic intervention that replenishes the insulin-producing pancreatic beta cells represents a cure for diabetes We propose to develop two distinct molecular scaffolds with demonstrated in vivo proof of concept for stimulating pancreatic beta-cell proliferation. A series of phenylbenzamides, discovered in an unrelated hepatic steatosis screen, were found to stimulate selective beta cell proliferation in rodents, isolated rat and human islets, and will be evaluated and optimized for efficacy and translational potential. The second series - chromenones, discovered in a Nkx6.1 promoter screen, have been shown to robustly stimulate beta-cell proliferation in rodent and human islets. We will perform medicinal chemistry optimization on both scaffolds to produce in vivo chemical probes with translational potential for human therapeutic use.

项目摘要/总结