Project ID CM-HD2023_27

ThemeCM-HD

Co Supervisor 1A Department of Diabetes/School of Cardiovascular and Metabolic Medicine & SciencesWebsite

Co Supervisor 1B Department of Nutritional SciencesWebsite

The role of dysregulated mitochondrial function inthe development of diabetic kidney disease

Scientific basis: Diabetic kidney disease (DKD), a major cause of renal failure, cardiovascular disease, and mortality, affects ~1/3rd of diabetes patients. Mitochondria are organelles which produce energy in the form of ATP and contain their own genome known as mitochondrial DNA (mtDNA). Damage to mitochondria plays a key role in the pathophysiology of kidney disease. We have identified a pathway of damage that indicates early damage to mtDNA as a key step in DKD. Preliminary studies indicate that it is possible to protect renal mtDNA from this damage and prevent subsequent bioenergetic deficit.

Aims: This PhD project will define early molecular pathways of damage that cause mitochondrial dysfunction using renal cell model systems and patient samples, the former will be used to identify compounds that can prevent this damage. iii)Techniques : The student will receive excellent training in cutting edge molecular, cell biology and computational methods including mammalian cell culture, DNA/RNA/protein isolation and analysis, real time qPCR, next generation sequencing, data analysis, biochemical assays, Cellular respiration assays using Agilent Seahorse, clinical data analysis, statistics, and bioinformatics. iv)

Figure show example of the kind of strategies that will be employed in year 1 for cell model work

Objectives:
1. Year 1.Develop in-vitro single cell-based model system(comparing human mesangial, proximal tubular and/podocytes) to track the longitudinal impact of hyperglycemia on mitochondrial and cellular function.
2. Year 2. Screen compound libraries using selected cell model for their ability to protect renal mitochondria from hyper glycemia induced damage by tracking longitudinal end points.
3. Year 3/4.Determine whether mtDNA damage, copy number/functional changes correlate with increased prevalence and severity of DKD in human clinical samples. Establish proof of concept with protective compounds. This work could lead to novel treatment strategies to reduce the incidence of DKD.

One representative publication from each co-supervisor:

• CZAJKA, A., AJAZ, S., GNUDI, L., PARSADE, C. K., JONES, P., REID, F. & MALIK, A. N. 2015. Altered Mitochondrial Function, Mitochondrial DNA and Reduced Metabolic Flexibility in Patients With Diabetic Nephropathy. EBioMedicine,2,499-512

• Version date: 28.04.22Sirt3-Sod2-mROS-Mediated Manganese Triggered Hepatic Mitochondrial Dysfunction and Lipotoxicity in a Freshwater Teleost.Zhao T, Lv WH, Hogstrand C, Zhang DG, Xu YC, Xu YH, Luo Z. Environ Sci Technol. 2022 Jun 2. doi: 10.1021/acs.est.2c00585. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/35653605/