Show simple item record

dc.contributor.authorBondzie, Philip Aprakuen_US
dc.date.accessioned2016-03-29T13:21:10Z
dc.date.available2016-03-29T13:21:10Z
dc.date.issued2014
dc.identifier.urihttps://hdl.handle.net/2144/15338
dc.description.abstractPeople of African ancestry (AA) are at greater risk of developing chronic kidney disease than those of non-AA. Much of this risk has been linked to specific genetic haplotypes on chromosome 22, near the genes APOL1, encoding apolipoprotein L1, and MYH9, encoding non-muscle myosin heavy chain IIA (NMHCIIA). The mechanisms by which the disease-associated chromosome 22 haplotypes promote kidney damage are unknown. Apolipoprotein L1 is a circulating protein with no known role in kidney function. However, the kidney disease-associated chromosome 22 haplotypes are protective against trypanosome infection, resulting in positive selective pressure for these haplotypes in western Africa, where trypanosome infection is endemic. In contrast, NMHCIIA may have an important role in glomerular function, and mutations in MYH9 are associated with glomerular disease, yet the disease-associated chromosome 22 haplotypes do not involve coding sequence variations in MYH9. With no clear disease-causing role for genes near the chromosome 22 risk locus, it is plausible that indirect mechanisms of gene regulation may be responsible for the increased disease risk. This study examines several potential pathways for kidney injury, including altered glomerular gene expression in carriers of chromosome 22 risk haplotypes, and the role of altered expression of MYH9 in podocyte cell biology and kidney disease. We found that carriers of chromosome 22 risk variants exhibited differential glomerular gene expression in pathways promoting kidney injury. We also found decreased glomerular NMHCIIA expression in human FSGS kidney biopsies, and altered cell structure and mechanical function when Myh9 is ablated in murine podocytes. Further, Myh9 podocyte deletion predisposed mice to glomerulopathy in response to injury by the DOCA-salt uninephrectomy model of hypertension. Taken together, these findings demonstrate direct and indirect effects of chromosome 22 risk variants on glomerular gene expression which promote kidney injury.en_US
dc.language.isoen_US
dc.subjectPathologyen_US
dc.subjectAfrican Americansen_US
dc.subjectAPOL1en_US
dc.subjectHypertensionen_US
dc.subjectKidney diseaseen_US
dc.subjectMYH9en_US
dc.subjectGlomerular capillary hypertensionen_US
dc.titleNew insights into the molecular regulation of kidney disease: contributions of APOL1 and MYH9en_US
dc.typeThesis/Dissertationen_US
dc.date.updated2016-03-12T07:11:36Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplinePathology & Laboratory Medicineen_US
etd.degree.grantorBoston Universityen_US


This item appears in the following Collection(s)

Show simple item record