| Mission
Statement |
Overview |
| Beta Cell Progenitors | Beta Cell Turnover |
| Cell Cycle Regulation of Beta Cells | Conclusions |
| Publications | The P.I. |
| Group Members | Contact Us |
| Directions | Parent
Organizations |
| Organizations
We Support |
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Mission Statement:
The overarching goal of our lab is to improve the health of children and adults with diabetes by contributing to the development of novel therapies that promote regeneration of the insulin-secreting beta-cells of the pancreas.
Overview
The islets of langerhans secrete insulin and other hormones to regulate glucose homeostasis. In type 1 diabetes beta cell mass is greatly decreased by autoimmune attack, resulting in an absolute insulin deficiency. Beta cell function and mass is also impaired in type 2 diabetes. Thus, beta cell regeneration is a fundemental challenge for both type 1 and type 2 diabetes. However, very little is known about the molecular signals that influence beta-cell growth and survival. Moreover, even the normal lifecycle of beta cells remains poorly understood.
How does beta-cell failure occur in either type of diabetes? Where do beta-cells come from? Do all beta-cells replicate? What signaling pathways influence beta-cell replication? How long to beta-cells live? What are the signals that influence beta cell survival? These are the questions our laboratory hopes to answer using genetic manipulation in mice and other model systems.
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Beta Cell Progenitors:
A major theme of our work includes studies to understand the lineage mechanisms of adult beta-cell growth and regeneration. Until recently it was not clear exactly where adult beta-cells came from during normal growth. Consequently, we initiated studies to resolve the lineage mechanism of adult beta-cell growth. To carry out these studies we developed a novel lineage tracing technique that uses sequential administration of different thymidine analogs. Remarkably, we do not observe any contribution to beta-cell mass in adult mice by specialized progenitors or stem cells. Instead, our studies reveal that self-renewal by the beta-cells is the major lineage mechanism of adult beta-cell mass expansion (Teta et al, Developmental Cell '07). We are currently expanding on this work, with the goal of studying beta-cell regeneration under a variety of physiological and pathological conditions.
We adapted techniques to detect incorporation of the thymidine analogues 5-chloro-2-deoxyuridine (CldU) and 5-iodo-2-deoxyuridine (IdU) into tissues of mice that were labelled with the analogues over prolonged periods via the drinking water. This strategy employs two different forms of anti-BrdU antisera raised in different species, which bind to CldU and IdU with different affinities (a). As each analogue could theoretically detect a distinct round of cell division, we speculated that this technique could allow detection of more than one round of cell division in vivo. If specialized progenitors substantially contribute to a mature tissue, recently divided cells should have undergone multiple rounds of cell division and therefore be doubly labelled (b). Alternatively, a mature tissue could renew or expand by self-renewal, and recently divided cells would not be comprised of cells that had undergone multiple rounds of cell division (c).
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Beta Cell Regeneration
Research efforts are also directed towards resolving the effect of aging upon beta-cell regeneration. In the past adult beta-cells were widely assumed to have a short lifespan and to undergo constant proliferation. However, our studies indicate that beta-cells of aged adult mice have extremely low rates of replication (Teta et al, Diabetes '05). Recent studies by our lab indicate that adaptive ß-cell proliferation is severely restricted with advanced age (Rankin et al, Diabetes '09). Thus a major challenge in the lab is to characterize the molecular mechanisms of this age dependent restriction in beta-cell regeneration capacity, and to determine if beta-cell mass can be expanded in aged mammals by unusual stimuli.
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Cell Cycle Regulation of Beta Cells
Another major research focus includes studies dedicated towards elucidating the molecular mechanisms of cell cycle control in ß-cell proliferation. Back in 2005 we published a report describing how cyclins D2 and D1 are essential for normal postnatal islet growth and function (Kushner et al, MCB 2005). More recently we have expanded on this work to describe how D-type cyclins are regulated in beta-cell (He ta al, Molecular Endocrinology '09). Other related work is focused on characterizing novel ß-cell mitogenic signals, with an emphasis on targets or pathways that might be amenable to pharmacological intervention.
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Conclusions:
Much remains to be learned in order to make beta-cell regeneration a reality for diabetes patients. Why do beta-cells proliferate so infrequently? Which beta-cells proliferate? To be honest, we have no idea. These questions suggest experimental avenues which we are actively pursuing with rigorous hypothesis-driven studies.
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Recent Publications :
He
LM, Sartori DJ, Teta M, Opare-Addo, LM, Rankin MM, Long SY, Diehl JA,
Kushner JA: Cyclin D2 Protein Stability Is Regulated In Pancreatic Beta
Cells. Molecular Endocrinology 2009 Notes: Article In Press.
Granger Anne, Kushner Jake A.: Cellular Origins of Beta Cell
Regeneration: a Legacy View of Historical Controversies. Journal of
Internal Medicine 266(4): 325-38, October 2009.
Rankin MM, Kushner JA: Adaptive beta-cell proliferation is severely
restricted with advanced age. Diabetes 58(6): 1362-72, Mar 2009.
Kiel Mark J, He Shenghui, Ashkenazi Rina, Gentry Sara N, Teta Monica,
Kushner Jake A, Jackson Trachette L, Morrison Sean J: Haematopoietic
stem cells do not asymmetrically segregate chromosomes or retain BrdU.
Nature 449(7159): 238-42, Sep 2007.
Teta Monica, Rankin Matthew M, Long Simon Y, Stein Geneva M, Kushner
Jake A: Growth and regeneration of adult beta cells does not involve
specialized progenitors. Developmental cell 12(5): 817-26, May 2007.
Teta Monica, Long Simon Y, Wartschow Lynn M, Rankin Matthew M, Kushner
Jake A: Very slow turnover of beta-cells in aged adult mice. Diabetes
54(9): 2557-67, Sep 2005.
Kushner Jake A: Beta-cell growth: an unusual paradigm of organogenesis
that is cyclin D2/Cdk4 dependent. Cell cycle 5(3): 234-7, Feb 2006.
Kushner Jake A, Ciemerych Maria A, Sicinska Ewa, Wartschow Lynn M, Teta
Monica, Long Simon Y, Sicinski Piotr, White Morris F: Cyclins D2 and D1
are essential for postnatal pancreatic beta-cell growth. Molecular and
cellular biology 25(9): 3752-62, May 2005.
Medline Search for Jake Kushner
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The Principal Investigator :
| Jake
Kushner |
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Education: 1987 B.A. University of California at Berkeley (Biochemistry) 1994 M.D. Albany Medical College Postgraduate Training and Fellowship Appointments: 1994-1997 Pediatrics Resident, Rhode Island Hospital, Brown University 1997-2000 Clinical Fellow in Pediatric Endocrinology, Children's Hospital, Boston 1998-1999 Postdoctoral Research Fellow, Laboratory of Marc Montminy, Joslin Diabetes Center, Department of Cell Biology, Harvard Medical School 1999-2003 Postdoctoral Research Fellow, Laboratory of Morris White, Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School Faculty Appointments: 2000-2003 Instructor in Medicine, Department of Pediatrics, Harvard Medical School 2004-present Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine 2004-present Faculty, Cell and Molecular Biology Graduate Group, Developmental, Stem Cell and Regenerative Biology Program Awards and Honors: 1999-2000 Lawson Wilkins Pediatric Endocrinology Society, Eli Lilly Fellowship 2001-2003 Juvenile Diabetes Research Foundation International Postdoctoral Research Fellowship 2003-2005 Charles H. Hood Foundation Child Health Research Grant 2003-2005 Lawson Wilkins Pediatric Endocrinology Society Clinical Scholar Award 2003-2008 NIH Mentored Clinical Scientist Career Development Award 2003-2009 NIH Pediatric Research Loan Repayment Program (competitive renewal x 2) 2009 Member, American Society of Clinical Investigation UPENN Graduate School Teaching: 2005 CAMB 605. Faculty member of first year seminar series in the Cellular And Molecular Biology Graduate Program. 2007 CAMB 632, Course Co-Director. Cell Control by Signal Transduction Pathways. 2008 CAMB 632, Course Co-Director. Cell Control by Signal Transduction Pathways. 2009 CAMB 530, Course Co-Director. The Cell Cycle and Cancer. |
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Lab Members :
| Matthew Rankin, BA | Kim Rak, BA |
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| Research Technician | Research Technician |
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Alex Tuttle, BA |
Dan Sartori, BA |
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| Research Technician |
Research Technician |
| Anne
Granger PhD |
Alisa
Schiffman DO |
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| Postdoctoral Research Fellow | Pediatric Endocrinology Fellow |
| Di Zhou | Gina Kim |
| Undergraduate Research Fellow (U Penn) | Undergraduate Research Fellow (U Penn) |
| Shirley
Ahn |
Carol
Lam |
| Undergraduate Research Fellow (U Penn) | Undergraduate Research Fellow (U Penn) |
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Directions :
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The Children's
Hospital of Philadelphia
The Joseph Stokes Jr. Research Institute · Leonard and Madlyn Abramson Pediatric Research Center 3615 Civic Center Blvd. Philadelphia, PA 19104 |
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Contact Us:
| Children's
Hospital
of Philadelphia Division of Endocrinology, ARC 802c 3615 Civic Center Blvd. Philadelphia, PA 19104 USA email: last name immediately followed by first initial (and all one word) at mail dot med dot upenn dot edu example for a fictional person whose first name is "First" and last name is "Last": lastf@mail.med.upenn.edu Tel : 1 267 426 5717 Fax: 1 215 590 1605 Lab Tel: 215-590-4572 |
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Organizations We Support:
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