this is a RO1 research grant with the long-term objectives to identify new molecular pathomechanisms and their underlying genetic programs by which TGF-beta/Smad signaling pathways my mediate chronic progression of renal diseases. The overall hypothesis is that depletion of podocytes is a pathomechanism of chronic progression in glomerular diseases. Toxic/genetic insults in podocytes may activate autocrine TGF-beta and/or Smad7 to trigger polocyte apoptosis. TGF-beta secreted by injured podocytes may also provide a paracrine signal to promote mesangial matrix expansion. In contrast, primary endocapillary/mesangial injuries may activate TGF-B providing an autocrine signal for matrix expansion and a paracrine signal for secondary podocyte apoptosis. The first Specific Aim will test whether podocyte toxins induce injury/apoptosis by activation TGF-beta- and/or Smad7-dependent genetic programs. We will examine phenotypic features in control and Smad7-deficient podocytes after exposure to TGF-beta and the podocyte-toxins protamine sulfate and puromycin aminonucleoside, and we will identify the underlying genetic programs (gene expression profiles using cDNA microarrays. The second Specific Aim will test whether Smad7 mediates podocyte depletion associated with glomerulosclerosis in TGF-beta1 transgenic mice. Compound genetic mice carrying the TGF-beta1 transgene and Smad7 null alleles will be analyzed for the effect of Smad7 gene dosage on the development of TGF-beta1-induced glomerulosclerosis and interstitial fibrosis, focusing on in vivo podocyte damage and apoptosis indices. We will profile gene expression to identify Smad7-dependent genetic programs that may underlie Smad7-dependent phenotypic manifestations. The third Specific Aim will test whether podocyte defects and/or apoptosis are mediated by TGF-beta- and/or Smad7-dependent genetic reprogramming and these parameters correlate with progression of glomerulosclerosis in CD2AP knockout mice. We will quantitate podocyte damage and apoptosis indices, mesangial matrix expansion glomerulosclerosis indices and correlate these parameter with TGF-beta and Smad7 expression, and activation of genetic programs as determined by microarray analysis in CD2AP knockout mice at different stages of disease. All gene expression datasets (see Aim 1, 2 and 3) will be cross-referenced in a relational database. Genetic programs with i) putative roles in podocyte injury in vitro (Aim 1), ii) differential regulation according to genotype in compound TGF-beta1/Smad7 genetic mice (Aim 2), and iii) during stages of the progressive glomerulosclerosis in CD2AP knockout mice (Aim 3), will be queried to delineate genetic programs that may underlie structural defects and apoptosis in podocytes induced by epigenetic (protamine sulfate and puromycin aminonucleoside) or genetic (CD2Ap minus/minus) insults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK060043-04
Application #
6887647
Study Section
General Medicine B Study Section (GMB)
Program Officer
Rasooly, Rebekah S
Project Start
2001-08-01
Project End
2005-05-31
Budget Start
2004-02-01
Budget End
2004-05-31
Support Year
4
Fiscal Year
2003
Total Cost
$211,875
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Lan, Rongpei; Geng, Hui; Singha, Prajjal K et al. (2016) Mitochondrial Pathology and Glycolytic Shift during Proximal Tubule Atrophy after Ischemic AKI. J Am Soc Nephrol 27:3356-3367
Eden, Caroline; Johnson, Kipp W; Gottesman, Omri et al. (2016) Medical student preparedness for an era of personalized medicine: findings from one US medical school. Per Med 13:129-141
Casalena, Gabriella; Bottinger, Erwin; Daehn, Ilse (2015) TGF?-Induced Actin Cytoskeleton Rearrangement in Podocytes Is Associated with Compensatory Adaptation of Mitochondrial Energy Metabolism. Nephron 131:278-84
Dutta, Dipankar J; Zameer, Andleeb; Mariani, John N et al. (2014) Combinatorial actions of Tgf? and Activin ligands promote oligodendrocyte development and CNS myelination. Development 141:2414-28
Casalena, Gabriela; Krick, Stefanie; Daehn, Ilse et al. (2014) Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro. Am J Physiol Renal Physiol 306:F1372-80
Daehn, Ilse; Casalena, Gabriella; Zhang, Taoran et al. (2014) Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis. J Clin Invest 124:1608-21
Shi, Shaolin; Yu, Liping; Zhang, Taoran et al. (2013) Smad2-dependent downregulation of miR-30 is required for TGF-?-induced apoptosis in podocytes. PLoS One 8:e75572
Xie, Wei-Bing; Li, Zuguo; Shi, Ning et al. (2013) Smad2 and myocardin-related transcription factor B cooperatively regulate vascular smooth muscle differentiation from neural crest cells. Circ Res 113:e76-86
Gentle, Madeleine E; Shi, Shaolin; Daehn, Ilse et al. (2013) Epithelial cell TGF? signaling induces acute tubular injury and interstitial inflammation. J Am Soc Nephrol 24:787-99
Berthier, Celine C; Bethunaickan, Ramalingam; Gonzalez-Rivera, Tania et al. (2012) Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis. J Immunol 189:988-1001

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