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Diabetic Nephropathy

What is the best way to collect patient samples?

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 »

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Diabetic Nephropathy

It is easier to find genes in DN for T1D than T2D?

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?

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Diabetic Nephropathy

Will systems biology discover new pathways and targets for DN?

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 »

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Diabetic Nephropathy

What are the key genetic and epigenetic determinants of DN?

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 »

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Diabetic Nephropathy

What is the role of the tubule in early DN?

The primary focus of the pathophysiology of diabetic renal disease has been on the glomerulus. Albuminuria has been shown to be a very sensitive biomarker of proximal tubule injury. Early changes in the proximal tubule may lead to secondary pathology which is typical for diabetic nephropathy. Thus the tubule may represent a therapeutic target for early diabetes.

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Diabetic Neuropathy

Demyelination

Demyelination is a prominent feature of clinical neuropathy, but absent from rodent models of diabetes (barring occasional reports of fixation artifact). Some markers of Schwann cell fidelity are disrupted, but myelin remains resplendently unchanged in the face of long periods of excess glucose exposure. Do we have to resort to the usual handwaving of "absoute duration of diabetes" being an explanatory factor when the ...more »

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Diabetic Nephropathy

How do we promote translation in DN?

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 »

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Diabetic Nephropathy

Can miRNA signatures be exploited to diagnose and treat DN?

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 »

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Diabetic Complications (General)

How does diabetes affect regeneration and repair?

Tissue injury in diabetes results from cell damage and death, impaired communication among cells, dysfunction of nerves and blood vessels, and detrimental responses to systemic signals, such as inflammation. The development of the clinical manifestations depends on tissue-specific responses to injury and impairments in repair and regenerative processes. The knowledge base of the pathologic process in different tissues ...more »

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Diabetic Nephropathy

Can stem cells repair and reverse DN?

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 »

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Diabetic Nephropathy

What new technologies will lead the field of DN forward?

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 »

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Diabetic Nephropathy

How will personalized medicine alter patient care in DN?

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 »

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Diabetic Nephropathy

Is mitochondrial (dys)function a major component of DN

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 »

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Diabetic Nephropathy

Are immunologic pathways causative factors in DN?

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 »

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Diabetic Nephropathy

Is autophagy a major contributor to DN and its progression?

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.

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Diabetic Nephropathy

Can biomarkers predict type 2 diabetic nephropathy

The value of currently available urine biomarkers that identify those at risk for diabetic nephropathy is increasingly called into question. The development of new urine and plasma biomarkers to predict diabetic nephropathy may shed light on disease mechanisms. Also, rational clinical trial design will be made possible by such markers.

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Diabetic Nephropathy

Can we develop "humanized mice" for the study of DN?

While the mouse has many advantages, the human diabetic nephropathy phenotype has been difficult to faithfully replicate in the mouse using candidate gene approaches. Future work should focus on developing "humanized mice," in which loci associated with human diabetic complications are knock-in to the mouse. These animals could then be used to study mechanisms and therapeutics using systems biology approaches.

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Diabetic Nephropathy

A role for the study of non-mammalian model systems in DN?

Non-mammalian model organisms have been underutilized to understand diabetic nephropathy pathogenesis. These simple model organism systems that permit ease of genetic manipulation, rapid throughput and precise measurement of phenotypes. Work published earlier this year (PNAS 107: 775, 2010) demonstrated that type 2 DM risk loci could be characterized in zebrafish. Interestingly, this study demonstrated this study shows ...more »

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