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Pediatrics - Endocrinology

Houston, Texas

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Diabetes & Endocrinology
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Jake Kushner, M.D.

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Jake Kushner, M.D.

Chief, Pediatric Diabetes and Endocrinology

Associate Professor of Pediatrics

Associate Professor of Molecular and Cellular Biology

McNair Medical Institute Scholar

Faculty,Graduate Program in Molecular and Cellular Biology

Faculty, Graduate Program in Immunology

Clinical Service Area

Diabetes & Endocrinology

Education

B.A., University of California at Berkeley
M.D., Albany Medical College
Resident in Pediatrics, Brown University, Rhode Island Hospital
Clinical Fellow in Pediatric Endocrinology, Harvard Medical School, Children's Hospital, Boston
Research Fellow, Harvard Medical School, Joslin Diabetes Center and Howard Hughes Medical Institute

Board Certification

American Board of Pediatrics, Pediatric Endocrinology

Professional Society Memberships and Elected Positions

  • Member, Lawson Wilkins Pediatric Endocrine Society
  • Member, American Society of Clinical Investigation
  • Member, Society for Pediatric Research
  • President-Elect, Society for Pediatric Research

Clinical Interests

  • Type 1 Diabetes
  • Pediatric Endocrinology
  • Cystic Fibrosis Related Diabetes

Reseach Interests

The overarching goal of our research is to improve outcomes of diabetic patients. We hope to discover pathways capable of promoting function or regeneration of the insulin-secreting pancreatic beta cells in diabetic patients. Our work focuses upon mitogenic signals, cell cycle regulation, the role of somatic stem cells and the effects of aging in islets.

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 postnatal life. We have carried out lineage tracing studies in adult mice under various conditions with numerous complementary tools. Remarkably, we do not observe any contribution to beta cell growth in adult mice from specialized progenitors or putative tissue stem cells. Instead, we find that self-renewal is the major lineage mechanism of adult beta cell mass expansion. We have recently expanded on this work and find no contribution from specialized progenitors after pancreatic injury. Ongoing studies aim to characterize the lineage mechanism of beta cell regeneration under a variety of physiological and pathological conditions. Self-renewal may be an underappreciated developmental mechanism to maintain important tissues in the body such as the esophageal epithelium.

Influenced by observations that beta cell mass expansion largely occurs via self-renewal, we are directing considerable effort to understanding the molecular signals that influence adult beta cell growth. We have carried out studies dedicated towards elucidating the molecular mechanisms of cell cycle control in beta cell proliferation. New work focuses upon on novel beta cell mitogenic signals, with an emphasis on discovery of targets or pathways that might be amenable to pharmacological intervention.

Extensive research efforts are 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. Additional studies indicate that adaptive beta cell growth is severely restricted with advanced age. Thus a major challenge is to characterize the molecular mechanisms of this age-dependent restriction in beta cell regeneration.

Finally, we are interested in the signals that promote beta cell survival. Pancreatic beta cell death is a central but enigmatic component of the pathogenesis of type 1 and type 2 diabetes mellitus. Surprisingly, little is currently known about the cell-specific mechanisms that govern beta cell survival. Turnover of beta cells, the balance between renewal and death, is a tightly controlled process. Indeed, beta cell turnover is exceedingly low in human beta cells, suggesting that tissue-specific factors might act within beta cells to tonically suppress apoptosis. Recent work by our group reveals that GATA transcription factors have important but non-essential roles to promote ER integrity and beta cell survival in a tissue-specific manner, and that GATA factors likely contribute to T1DM pathogenesis.

(View links to related publications below.)

Honors and Awards

  • Pediatric Endocrinology Society, Eli Lilly Fellowship, 1999
  • Juvenile Diabetes Research Foundation International Postdoctoral Research Fellowship, 2001
  • Pediatric Endocrinology Society Clinical Scholar Award, 2003
  • Charles H. Hood Foundation Child Health Research Grant, 2003
  • NIH Mentored Clinical Scientist Career Development Award, 2003
  • National Institutes of Health (NIH) Pediatric Research Loan Repayment Program, 2003 (competitive renewal 2005 & 2007)
  • Basil O'Connor Career Development Award, March of Dimes, 2005
  • Elected Membership, Society for Pediatric Research, 2006
  • Elected Membership, American Society of Clinical Investigation, 2009
  • McNair Medical Institute Scholar, Baylor College of Medicine, 2011

Publications

  1. Kushner JA, Ciemerych MA, Sicinska E, Wartschow LM, Teta M, Long SY, Sicinski P, White MF. Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol Cell Biol. 2005 May; 25(9): 3752-62. PMID:15831479
  2. Teta M, Long SY, Wartschow LM, Rankin MM, Kushner JA. Very slow turnover of beta-cells in aged adult mice. Diabetes. 2005 Sep; 54(9): 2557-67. PMID: 16123343.
  3. Kushner JA. Beta-cell growth: an unusual paradigm of organogenesis that is cyclin D2/Cdk4 dependent. Cell Cycle. 2006 Feb; 5(3): 234-7. PMID: 16410729.
  4. Ablamunits V, Sherry NA, Kushner JA, Herold KC. Autoimmunity and beta cell regeneration in mouse and human type 1 diabetes: the peace is not enough. Ann N YAcad Sci. 2007 Apr; 1103: 19-32. Review. PMID: 17376841.
  5. Teta M, Rankin MM, Long SY, Stein GM, Kushner JA. Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell. 2007 May; 12(5): 817-26. PMID: 17488631.
  6. Rankin MM, Kushner JA. Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes. 2009 Jun; 58(6): 1365-72. PMID: 19265026.
  7. 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. Mol Endocrinol. 2009 Nov; 23(11): 1865-75. PMID: 19628581.
  8. Kushner JA, Weir GC, Bonner-Weir S. Ductal origin hypothesis of pancreatic regeneration under attack. Cell Metab. 2010 Jan; 11(1): 2-3. PMID: 20085728.
  9. Perl S, Kushner JA, Buchholz BA, Meeker AK, Stein GM, Hsieh M, Kirby M, Pechhold S, Liu EH, Harlan DM, Tisdale JF. Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating. J Clin Endocrinol Metab. 2010 Oct; 95(10): E234-9. PMID: 20660050.
  10. Rankin MM, Kushner JA. Aging induces a distinct gene expression program in mouse islets. Islets. 2010 Nov 1; 2(6): 4-11. PMID: 21099336.
  11. Kushner JA. Development. Esophageal stem cells, where art thou? Science. 2012 Aug 31;337(6098):1051-2. PubMed PMID: 22936766.
  12. Rankin MM, Wilbur CJ, Rak K, Shields EJ, Granger A, Kushner JA. β-Cells Are Not Generated in Pancreatic Duct Ligation-Induced Injury in Adult Mice. Diabetes. 2013 May;62(5):1634-45. doi: 10.2337/db12-0848. Epub 2013 Jan 24. PubMed PMID:23349489; PubMed Central PMCID: PMC3636617. Cover image.
  13. Kushner JA. The role of aging upon β cell turnover. J Clin Invest. 2013 Mar 1;123(3):990-5. doi: 10.1172/JCI64095. Epub 2013 Mar 1. Review. PubMed PMID: 23454762; PubMed Central PMCID: PMC3582123.
  14. Sartori DJ, Wilbur CJ, Long SY, Rankin MM, Li C, Bradfield JP, Hakonarson H,Grant SF, Pu WT, Kushner JA. GATA factors promote ER integrity, β-cell survival, and contribute to type 1 diabetes risk. Mol Endocrinol. 2013 Nov 27. [Epub ahead of print] PubMed PMID: 24284823.

Contact Information

6701 Fannin St., 11th Floor
Houston, TX 77030-2399

Clinic: 832-822-3670
Fax: 832-825-9069

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