Investigators - Basic science - shankland

Stuart J. Shankland, MD, MBA

Shankland Lab Website

Rebuilding a Kidney Consortium


Project 1: Glomerular epithelial cell regeneration and progenitors

Podocytes are terminally differentiated epithelial cells who’s function include limiting the passage of albumin from the intravascular space, to the extravascular urinary space. However, injury in several primary proteinuric glomerular diseases such as FSGS and secondary glomerular diseases such as diabetes, oftentimes results in podocyte depletion due to events such apoptosis, detachment and altered autophagy. In contrast to other kidney cells, podocytes do not have the cell cycle machinery to adequately proliferate. Thus, renewal of podocyte number in adults much rely on the regeneration by progenitor cells. Our laboratory is studying two potential podocyte progenitor cells: cells of renin lineage that reside in the juxta-glomerular compartment, and glomerular parietal epithelial cells, more immediate neighbors for podocytes. Using a number of specific reporter mice, we can show that following the depletion of podocyte number in experimental models of glomerular disease, a subset of cells of renin lineage move to the intraglomerular compartment, where they begin to express markers of podocytes, as well as acquire the characteristic ultrastructure of these highly specialized cells. A subset of cells of renin lineage in the glomerulus also begin to express markers of parietal epithelial cells Taken together, our research shows that both cells of renin lineage and parietal epithelial cells serve a role as podocyte progenitors. Studies are ongoing to determine the underlying pathways and mechanisms, and ways in which regeneration can be augmented, as the ultimate goal is to improve the outcomes of patients with glomerular disease.

Project 2: Cell cycle proteins in podocyte biology

Our earlier work focused on the more “classic” cell cycle regulatory proteins, where we showed that following injury to podocytes, levels of specific cyclin-dependent kinase inhibitors (p21, p27, p57) increased, thereby inhibiting the activity of cyclin-cyclin dependent kinase complexes. This limits and prevents podocyte proliferation, leading to an overall depletion in cell number. More recently, we reported that podocytes constitutively express cyclin I and cdk5, considered more “atypical” cell cycle proteins. Our data shows for the first time that cyclin I activates cdk5, and that active cyclin I-cdk5 is essential for podocyte survival following stress in disease. This novel biological role is governed by c ertain MAPK pathways which in turn regulate critical pro-survival Bcl-2 family proteins. We are exploring other pathways whereby cdk5 is activated, including p35, and how the interplay of cyclin I and p35 might determne the subcellular localization and thus function of their partner cdk5.

Project 3: Role of pericytes in tubulo-interstitial scarring

Together with Dr. Jeremy Duffield, we are continuing a body of work showing that kidney pericytes lead a dual life. On one hand they are vital for normal peri-tubular vascular function, where they surround these vessels and maintain their survival. Yet, under certain disease-induced stress situations, pericytes become more fibroblast-like, and become pro-fibrotic cells. This leads to progressive interstitial fibrosis and a decrease in kidney function.

Project 4: Diabetic kidney disease

Together with Dr. Charles Alpers, our laboratory is exploring the consequences of reduced podocyte number, and how these cells might be replaced through regeneration by progenitor cells. In experimental type 2 diabetic nephropathy, we recently reported that parietal epithelial cells might be a candidate podocyte progenitor, and studies are ongoing using specific reporter mice to address this hypothesis.

Current Funding

NIH - RO1 - Renewal Shankland (PI) (7/1/11 - 6/30/16)
Cell Cycle and Podocyte Apoptosis
Studies are designed to determine the role of Cyclin I and CDK5, and when active, this complex enhances Survival of terminally differential cells such as podocytes. The signaling pathways will be delineated. Cell culture and experimental models will be used to delineate this further.

NIH - RO1 - DK056799-10 Shankland (PI) (9/1/11 - 4/30/16)
Cell Cycle and Podocytes
The goal of the first aim of this competitive renewal is to show a new paradigm for cell cycle protein function, based on our preliminary data In summary, the studies proposed will advance scientific knowledge in glomerular diseases, and in cell cycle protein research. The overall goal of the second aim is to show new regulatory paradigms for cyclin I-p35-cdk5, which play a fundamental role in glomerular and brain development. In summary, the studies proposed will advance scientific knowledge in glomerular diseases, and in cell cycle protein research.

NIH - T32 - DK007467-31 (PI) (7/1/14 - 6/30/19)
Research Training in Renal Disease
This is a training grant that supports research training for three M.D. post-graduate fellows who undergoperiods of both renal and basic science research training.

NIH – R01- DK083391-01A2 Alpers (PI) (9/15/11-8/31/16)
Podocyte depletion and regeneration during evolution and reversal of diabetic nephropathy
This grant explores mechanisms underlying reversibility (replacement of kidney cell populations that are typically lost in human and experimental diabetic kidney disease) with emphasis on the podocyte, a unique cell type in the kidney. This grant also focuses on testing new therapies, based on correcting metabolic injuries to mitochondria (an organelle present within all cells), that are specifically directed to podocyte mitochondria, as a way to promote reversal of diabetic kidney disease.

NIH – R01- DK093493-02 Shankland (PI) (9/03/12 - 6/30/17)
Pericyte-endothelial cross talk in vascular stability after kidney injury
These studies will investigate the mechanisms by which pericytes nurture kidney blood vessels and the mechanisms by which they detach in response to injury and thereafter fail to nurture. In understanding these processes we hope to develop new therapies to treat kidney diseases.

NIH – R01- DK097596-01A1 Shankland (PI) (7/1/14 - 6/30/19)
Juxta-glamerular cells serve as glomerular epithelial cell progenitors in glomerular disease
The purpose of this proposal is to study the existing problem of age-related podocyte depletion in a completely new context. The goal is to prove that with advancing age, kidney regeneration, and thus repair, is inadequate because progenitors are unable to replace and restore glomerular podocytes. We anticipate that the results will provide compelling evidence for a new paradigm in aging kidneys in which recently identified progenitors are unable to adequately regenerate to replace podocytes, which leads to glomerulosclerosis and reduced kidney function.

Past Funding

NIH ARRA Grant (DK056799-07S1) (09/21/09-08/31/11)
Cell Cycle and Podocyte Apoptosis
Studies are designed to determine the role of Cyclin I and CDK5, and when active, this complex enhances survival of terminally differential cells such as podocytes. The signaling pathways will be delineated. Cell culture and experimental models will be used to delineate this further.

NIH R01 Grant (DK056799-05A1) Shankland (PI) (09/30/07 – 6/30/11)
Cell Cycle and Podocyte Apoptosis
The overall goal of this grant is to delineate new paradigms in the regulation of podocyte survival and death, so that ultimately new strategies can be developed to prevent podocyte loss, enhance kidney survival, and reduce kidney disease.

NIH Basic Training Grant (T32 DL07467-21) Shankland(PI) (09/01/2009–8/31/13)
Nephrology Training 03
This is a training grant that supports research training for three M.D. post-graduate fellows who undergo periods of both renal and basic science research training.

NIH NIDDK ARRA R21 (DK081835-01A2) Shankland (PI) (08/15/09 – 06/30/11)
New Thoughts on Parietal Cells
The precise biological role of parietal epithelial cells (PECs) are not well understood in health or disease. The main goal of this grant is to show that PECs are required to limit filtered proteins ‘escaping’ into the peri-glomerular space. We will test the hypotheses that the intra-cellular tight junctions in PECs, together with the underlying Bowman’s Basement membrane, forms a second barrier to proteinuria. We will also test the hypothesis that PECs actively take up filtered albuminuria which injures them by inducing apoptosis.

1 F32 DK072788-01 Shankland (PI) (9/19/05-12/30/07)
HHS Logar Fellow

DHHS 5901 Letter of Credit (LOC) Shankland (PI) (4/1/2008-3/31/09)
7th Intl Podocyte Conference
This grant will be used to support the travel of junior investigators to attend scientific conference.

AHA – Established Investigator Award 0340129N Shankland (PI) (1/01/03– 12/31/08)
Role of Cell Cycle in Podocyte Injury
The proposed studies are designed to test novel aspects of cell cycle proteins in disease, so that potential therapeutic interventions can be designed to reduce the incidence of renal failure.

NIH R01 grant DK 51096-05A2 Shankland (PI) (09/01/04-06/30/07)
Cell Cycle Control in Glomerular Disease
The major goal of this grant is to determine the expression and activity of specific cell cycle proteins in glomerular cell proliferation and differentiation in vitro and in vivo. Overlap: None.

Applied Molecular Genetics (AMGEN) Shankland (PI) (09/27/04-09/26/06)
Role of Erythropeitin (EPO) in Proteinuria
The overall goal of this grant is to test whether a decrease in endogenous EPO in renal disease augments loss of podocytes differentiation, preventing progressive proteinuria and scarring.

American Diabetes Association (7-04-RA-107-80-0572) Shankland (PI) (07/01/04-06/30/06)
Role of Podocytes in Diabetic Nephropathy
The overall goal of this grant is to delineate the mechanisms underlying the abnormalities in podocytes, utilizing cultured cells and animal models of diabetic nephropathy.

NIH R01 grant DK 60525-02 Shankland (PI) (07/01/02-06/30/06)
Mechanisms of Podocyte Injury
The major goals of this grant are to study the effect of stress-tension-induced injury on podocytes, and also to determine the role of novel cell cycle regulatory proteins in podocyte disease.

NIH R01 grant DK 56799-04 Shankland (PI) (05/01/00-02/28/05)
Cell Cycle Proteins and Glomerular Apoptosis
The major goal of this project is to show novel roles for specific cell cycle proteins in glomerular cell apoptosis beyond that of proliferation.

1-2001-395 Shankland (PI) (01/01/01-12/31/03)
Juvenile Diabetes Research Foundation (JDRF)
The Role of Cyclin Kinase Inhibitors in Diabetic Glomerular Hypertrophy
The major goal of this project will be to determine the nuclear mechanisms underlying the development of diabetic hypertrophy, with a focus on specific CDK inhibitors. Overlap: None.

NIH R01 grant DK 47659-10 Shankland (PI) (09/01/98-08/31/03)
Immunological Renal Diseases: Subproject #2, “The Role of Cell Cycle Proteins in Glomerular Epithelial Cell Growth”
The major goal of this project is to test the hypothesis that specific CDK-inhibitors p57-WT1 determine the proliferative capacity of the glomerular visceral epithelial cell.

NIH R01 grant DK 51096 Shankland (PI) (06/01/96-05/31/04)
Cell Cycle Control in Glomerular Disease
The major goal of this grant is to determine the expression and activity of specific cell cycle proteins in glomerular cell proliferation and differentiation in vitro and in vivo. Overlap: None.

NIH/NIDDK R13 (DK069139-01) Shankland (PI) (06/01/04-06/30/05)
“5th International Podocyte Conference”
This grant was used to support the travel of junior investigators to attend this scientific meeting.

NIH (R01) Grant; (DK 52121) Shankland (PI) (01/01/97-12/31/01)
Role of the Glomerular Endothelial Cell in Hemolytic Uremic Syndrome (HUS)
The goal was to determine the mechanisms of endothelial cell proliferation and apoptosis.

C. V. Therapeutics, Inc. Grant Shankland (PI) (01/01/00-12/31/00)
Role of Cell Cycle Proteins in Hemodialysis Vascular Stenosis
The study was designed to determine the role of cell cycle proteins in vascular access stenosis.

Publications

PubMed provides a list of Dr. Shanklandi's research publications

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