There has been an explosion of new genetic, biochemical, and cell biologic techniques. Appropriate systems biology tools are needed to facilitate integration of genotyping information, mRNA expression, microRNA expression, promoter analysis, proteome expression, and metabolome profiles in order to identify key biological processes and their interactions. In addition to better computational tools, a deeper understanding ...more »
Metabolic control alone does not predict an individual’s risk for diabetic complications. Family studies suggest that genetic factors play an important role in the predisposition for a specific type of complication and its progression. In addition to more classic genetics, research in this area has expanded to epigenetics and non-coding RNA. Epigenetic marks include modifications to the DNA or chromatin that do not ...more »
Identifying robust association between genetic variation and severe human CKD phenotypes has been hindered by lack of collections of patient sample collection of sufficient size to use effectively in GWAS. The community could address this issue by developing reproducible but simple clinical phenotyping criteria and collecting samples from ESRD patients in dialysis units. Contrast can be made to publicly available datasets ...more »
It has been difficult to identify SNPs with even modest effects in studies of type 2 diabetic nephropathy. One possible explanation is that patients with kidney disease who have type 2 diabetes may not have a single disease. Indeed the old biopsy data suggest that there is a diversity of diseases in this population. Should gene finding efforts focus exclusively on type 1 diabetic nephropathy for the short term?
Mechanisms should be established to support research on drug and biologic development that will not be supported by industry. For example, expansion of programs such as the NIH-supported Type 1 Diabetes Rapid Access to Intervention Development (T1D-RAID) program, and establishment of clinical trial networks, would allow potential therapies to be developed and tested in early Phase I and II trials that could lead to NIH ...more »
MicroRNAs are short ribonucleotides that bind to messenger RNA to modify protein translation or promote RNA degradation. Knowledge of the function and regulation of miRNA is rapidly expanding. They appear to be sensitive to the extracellular environment and could be important regulators of a cell’s response to diabetes. Can miRNA signatures detect early signs of DN? Can knowledge of miRNA signatures be translated ...more »
Normally, metabolic and ischemic insults stimulate repair and regeneration. In diabetes, however, these processes are impaired. Recent advances in cell reprogramming hold great promise for future cell replacement therapies. How are specific populations of stem/progenitor cells affected by diabetes? Are these abnormalities reversible through optimal diabetes treatment or therapies targeted to stem/progenitor cells? ...more »
Translation of the knowledge of the molecular consequences of diabetes to effective therapies requires better measures of disease progression, faithful models of the molecular and cellular pathology, and application of cutting-edge technologies. Validated biomarkers and surrogate end points will allow rapid screening of clinical interventions prior to larger clinical trials, and can assess risk factors and treatment adequacy ...more »
One explanation for the discordant response of agents that treat complications in rodents versus humans is that deleterious pathways that are responsive to a certain drug may be widely expressed in inbred animal models, but expressed in only a small number of individuals. Should some agents be tested in primates or some other larger mammal? Pharmacogenomic, pharmacometabolomic, and pharmacoproteomic approaches could ...more »
Genetic mutations in mitochondrial fission/fusion proteins and changes in ROS production have been linked to diabetic complications. Why does the apparently global pathogenic mechanism of increased mitochondrial activity have variable consequences in different cell types? Can we develop better tools to assess mitochondrial function, transport, number, and fission/fusion states? Can we improve mitochondrial function ...more »
The abundance of molecular pathways affected by diabetes presents the challenge of understanding complex interactions among the pathways, but also the opportunity of providing multiple and potentially complementary targets for drug development. How do the identified molecular pathways associated with diabetic nephropathy interact within each cell and does this vary for different cell types? Are there undiscovered molecular ...more »
Autophagy was discovered in yeast as a stress response and may contribute to the excess of cell death and progression of complications. The human homologues of yeast autophagy genes and drugs known to affect autophagy are available to test the role of autophagy in diabetic nephropathy.