This project addresses the """"""""Applying Genomics and Other High Throughput Technologies"""""""" thematic area. HIV-associated nephropathy (HIVAN) is a unique disease that results from the interplay of environmental factors (HIV), host responses to the virus, and a genetic predisposition, primarily in individuals of African descent. As a result of these complex interactions, a number of maladaptive biological responses occur that produce the collapsing glomerulosclerosis with pseudocrescent formation, microcystic tubular dilatation, and prominent interstitial inflammation that we recognize pathologically as HIVAN. Recent Genome-wide analyses have identified a strong association of the gene MYH9, which encodes non-muscle myosin heavy chain IIA (Myosin-9), with idiopathic and HIV-associated FSGS in African-Americans. Despite the strong association of MYH9 polymorphisms with the risk of HIVAN, two copies of the MYH9 E-1 risk allele is not sufficient for nephropathy. Additionally, there are no data on the functional consequence of MYH9 risk alleles on Myh9 transcript or protein function. To understand how the MYH9 risk allele in combination with HIV-1 infection promotes alteration of the podocyte regulatory network we plan to use next generation sequencing to explicitly define the entire RNA- transcriptome and small non-coding RNAs and compare this between individuals with and without the risk allele. We will use systems biology models to integrate new data with existing data from our laboratory and in the published literature. Our goals are: 1) Determine variability in podocyte transcriptome and regulatory networks in HIV-infected and control human podocytes from patients with or without the MYH9 risk allele when environmental factors are controlled. We hypothesize that even if the environmental factors are controlled, there will still be a variable response to HIV-infection. We will also determine if there is differential miRNA expression in HIV-1 in podocytes with or without the MYH9 risk allele. 2) Determine the mechanism by which MYH9 is downregulated.
The proposed research has the potential to significantly impact the health of people of African descent, who face a disproportionate burden of HIV infection and end-stage renal disease. Findings from the proposed research are likely to provide insights into the increased susceptibility to kidney disease and end-stage renal disease among people of African descent.
| Clark, Neil R; Hu, Kevin S; Feldmann, Axel S et al. (2014) The characteristic direction: a geometrical approach to identify differentially expressed genes. BMC Bioinformatics 15:79 |
| Gu, Leyi; Dai, Yan; Xu, Jin et al. (2013) Deletion of podocyte STAT3 mitigates the entire spectrum of HIV-1-associated nephropathy. AIDS 27:1091-8 |
| Jiang, Song; Chuang, Peter Y; Liu, Zhi-Hong et al. (2013) The primary glomerulonephritides: a systems biology approach. Nat Rev Nephrol 9:500-12 |
| Zhong, Yifei; Chen, Edward Y; Liu, Ruijie et al. (2013) Renoprotective effect of combined inhibition of angiotensin-converting enzyme and histone deacetylase. J Am Soc Nephrol 24:801-11 |
| Dannenfelser, Ruth; Clark, Neil R; Ma'ayan, Avi (2012) Genes2FANs: connecting genes through functional association networks. BMC Bioinformatics 13:156 |
| He, John Cijiang; Chuang, Peter Y; Ma'ayan, Avi et al. (2012) Systems biology of kidney diseases. Kidney Int 81:22-39 |
| Clark, Neil R; Dannenfelser, Ruth; Tan, Christopher M et al. (2012) Sets2Networks: network inference from repeated observations of sets. BMC Syst Biol 6:89 |
| Chen, Edward Y; Xu, Huilei; Gordonov, Simon et al. (2012) Expression2Kinases: mRNA profiling linked to multiple upstream regulatory layers. Bioinformatics 28:105-11 |
| Jin, Yuanmeng; Ratnam, Krishna; Chuang, Peter Y et al. (2012) A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med 18:580-8 |
| Medapalli, Raj K; He, John C; Klotman, Paul E (2011) HIV-associated nephropathy: pathogenesis. Curr Opin Nephrol Hypertens 20:306-11 |
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