2011 Research Annual Report

Division Data Summary

Research and Training Details

Number of Faculty12
Number of Joint Appointment Faculty1
Number of Support Personnel29
Direct Annual Grant Support$1,656,184
Direct Annual Industry Support$124,528
Peer Reviewed Publications15

Clinical Activities and Training

Number of Clinical Fellows10
Inpatient Encounters2,605
Outpatient Encounters11,724

Division Photo

Endocrinology Division.

Row 1: D Elder, N Crimmins

Row 2: N Yayah Jones, I Gutmark-Little, A Sanghavi Shah

Row 3: M Rutter, P Backeljauw, S Lawson

Row 4: D Klein, L Dolan, J Katz


Significant Publications

Kim HK, Gottliebson W, Hor K, Backeljauw P, Gutmark-Little I, Salisbury SR, Racadio JM, Helton-Skally K, Fleck R. Cardiovascular anomalies in Turner syndrome: spectrum, prevalence, and cardiac MRI findings in a pediatric and young adult populationAmerican Journal of Roentgenology. 196:454-50. 2011.
This paper provides a detailed description of the type and frequency of cardiovascular anomalies in Turner syndrome that may lead to premature morbidity and mortality.
Sherafat-Kazemzadeh R, Schroeder JK, Kessler CA, Handwerger S. Parathyroid hormone-like (PTHLH) represses decidualization of human uterine fibroblast cells by autocrine/paracrine mechanismJournal of Clinical Endocrinology and Metabolism. 96:509-14. 2011.
PTHLP is found in large concentrations in human endometrial Stromal cells during decidualization.  The role of PTHLP is not known.  This paper demonstrates for the first time that PTHLP represses the induction of human decidualization, stimulates stromal cell apoptosis, and limits the extent of uterine stromal cell differentiation.
Katz JD, Ondr JK, Opoka RJ, Garcia Z, Janssen EM.  Cutting edge: merocytic dendritic cells break T cell tolerance to beta cell antigens in nonobese diabetic mouse diabetes. Journal of Immunology. 15:1999-2003. 2010.
In this study Dr. Katz and his research team identified a critical sub-population of dendritic cells responsible for mediating peripheral tolerance to beta cell antigen in vivo.
Shah AS, Dolan LM, Gao Z, Kimball, Urbinia EM.  Clustering of risk factors: a simple method of detecting cardiovascular disease in youthPediatrics. 127:e312-8. 2011.
This paper demonstrates that clustering of risk factors is as reliable but simpler method for assessing cardiovascular risk than the Pathobiological Determinants of Atherosclerosis in Youth score, presently the accepted method of assessing cardiovascular risk.
Urbina EM, Kimball TR, Khoury PR, Daniels SR, Dolan LMIncreased arterial stiffness is found in adolescents with obesity and obesity-related type2 diabetesJournal of Hypertension. 28:1692-8. 2010.
This manuscript establishes the presence of a progressive increase in vascular stiffness in youth from lean to obese to obese type 2 that cannot be explained by traditional cardiovascular risk factors.

Division Collaboration

Reproductive Sciences » S.K. Dey, MD; Sanjoy Das, PhD
Research
Neonatology & Pulmonary Biology » Cindy Bachurski, PhD; Jeffrey Whitsett, MD
Research
Biomedical Informatics » Bruce Aronow, PhD; Anil Jegga, MS, DVM
Research
Pathology » Jerzy Stanek, MD, PhD
Research
Molecular and Developmental Biology » James Wells, PhD
Research
Healthworks; Preventive Cardiology; Gastroenterology » Holly Ippisch, MD; Stavra Xanthakos, MD, MS; Robert Siegel, MD
Center for Better Health and Nutrition clinical collaboration
Center for Adherence in Psychiatry » Denny Drotar, PhD; Korey Hood, PhD
Research
Pulmonary » Mike Seid, PhD; James Acton, MD; Jamie Wooldridge, MD
Growth hormone therapy in patients with cystic fibrosis; Cystic fibrosis insulin study
General Pediatrics » Maria Britto, MD, MPH
Research
ICU » Derek Wheeler, MD
Research
Pharmacy » Anne Lesko, PharmD; Shannon Saldana, PharmD, MS, BCPP
Research
Adolescent Gyn; Urology » Lesley Breech, MD; Curtis Sheldon, MD
Clinical collaboration - Disorders of Sexual Differentiation Clinic
Gastroenterology » Lee Denson, MD
Study of the effects of growth hormone on patients with Crohn's disease
Emergency Medicine » Mike Gittelman, MD; Wendy Pomerantz, MD
Injury prevention project (RWJ sponsored) in an obesity prevention project in an area experiencing health disparities
Psychiatry » Mike Sorter, MD; Mary Matias-Akhtar, MD
Project to see if Metformin given at the initiation of anti-psychotic treatment can prevent weight accretion, which occurs commonly in children on these agents
Adolescent Medicine » Heidi Kwalkorf, PhD; Lorah Dorn, RN, PhD
NIH multicenter study of bone mineral in healthy children and adolescents; grant application regarding smoking and pubertal development
Rheumatology » Hermine Brunner, MD
NIH funded grant of Triptorelin therapy in lupus patients
Hematology Oncology; Hematology Oncology » Franklin Smith, MD; Richard Harris, MD; Stella Davies, MD; Parinda Mehta, MD

Funded study of oxandrolone therapy in children with Fanconi anemia

Research, database, and multicenter care of patients with Fanconi Anemia and other bone marrow failure syndromes

Mayerson Center » Kathi Makoroff, MD
Pfizer funded study shaken infants
Physical Medicine and Rehabilitation » Linda Michaud, MD
Pfizer funded study of endocrine function after traumatic brain injury
Neurology » Brenda Wong, MD
Development of research regarding Duchenne Muscular Dystrophy
Cardiology » Elaine Urbina, MD; Thomas Kimball, MD; John Morrison, PhD

Clinical management protocol for cardiac disease in Turner syndrome

The epidemiology of peripheral cardiovascular disease in youth with a specific emphasis on the role of obesity, insulin resistance and diabetes

The epidemiology of central (heart) cardiovascular disease in youth with a specific emphasis on the role of obesity, insulin resistance and diabetes

The ability of pre-teen variables to predict the development of obesity, insulin resistance, diabetes and cardiovascular disease

Epidemiology and Biostatistics » Lisa Martin, PhD; Jane Khoury, PhD; Jessica Woo, PhD

Contribution of genetics to obesity in adolescents

The effect of maternal type 1 diabetes on adolescents and young adult offspring with a focus on obesity and carbohydrate metabolism

Creation of clinical database for the Comprehensive Weight Management Center

Psychology and Behavioral Medicine » Scott Powers, PhD
Eating behaviors in individuals 16 years of age with type 1 diabetes
Surgery » Thomas Inge, MD, PhD

Bariatric surgery in youth: safety, efficacy, and effect on carbohydrate and cardiovascular outcomes

International Hypothalamic Obesity Registry

Faculty Members

Stuart Handwerger, MD, Professor
Professor of Cancer and Cell Biology
Research Interests Growth and thyroid disorders; perinatal endocrinology
Philippe Backeljauw, MD, Professor
Director, Cincinnati Turner Syndrome Center
Research Interests Growth disorders; disorders of bone and calcium metabolism; Turner Syndrome
Nancy Crimmins, MD, Assistant Professor
Research Interests Diabetes; obesity
Lawrence M Dolan, MD, Professor
Division Director, Robert and Mary Shoemaker Professor of Pediatrics
Research Interests Diabetes mellitus; non-insulin dependent diabetes; sexual development disorders; growth disorders; disorders of the thyroid; goiters; hypoglycemia
Deborah Elder, MD, Assistant Professor
Research Interests Diabetes; growth disorders; precocious puberty; calcium disorders
Jonathan Katz, PhD, Associate Professor
Director, Diabetes Research Center
Research Interests
David J Klein, MD, PhD, Associate Professor
Research Interests Diabetes mellitus; intensive diabetes management programs; early detection of renal disease; effects of diabetes mellitus on renal proteoglycan synthesis
Susan Rose, MD, Professor
Research Interests Hypothalamic pituitary function; thyroid disorders; disorders of growth or puberty; endocrine function in cancer survivors; endocrine function after head injury
Meilan Rutter, MD, Assistant Professor
Research Interests Calcium disorders; endocrine function in childhood cancer survivors; endocrine function in muscular dystrophy
Peggy Stenger, DO, Assistant Professor
Research Interests Growth disorders; disorders of sexual development; pubertal disorders; disorders of the thyroid; goiter
Nana-Hawa Yayah Jones, MD, Assistant Professor
Research Interests Adherence/compliance in type 1 diabetes
Iris Gutmark-Little, MD, Assistant Professor
Research Interests Airway and great vessel disorders in Turner syndrome

Joint Appointment Faculty Members

Jessica Woo, PhD, Assistant Professor
Epidemiology
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Significant Accomplishments

Turner Syndrome Research

The Turner Syndrome Center has investigated cardiovascular anomalies in Turner syndrome (TS) patients by cardiac MRI, including aortic abnormalities and partial anomalous pulmonary venous return (PAPVR).   The prevalence of PAPVR was found to be 18 percent. Six of the newly diagnosed patients had not been diagnosed by echocardiogram. Another study found  the prevalence of hypertension in TS girls  to be under-recognized. More attention should be given to careful determination, interpretation and follow-up of blood pressure monitoring in TS girls, including a recommendation to manually perform all blood pressure measurements in TS girls . A prospective study comparing the prevalence of vasculopathy in TS patients showed evidence of increased arterial stiffness. This puts TS girls at greater risk for cardiovascular disease later in life.  As a next step, measurements of TS-specific comorbidities will be evaluated in an attempt to determine the specific at-risk TS population. These studies underscore the importance of a multidisciplinary approach to TS care, together with the development of a large patient database.  New studies being developed will focus on further evaluation of large vessel disease, assessment of airway dysfunction and studies looking at abnormalities of glucose metabolism.

Placental Development in Normal and Pathologic Pregnancies

Many pathologic conditions of pregnancy that result in infant morbidity and mortality, such as preeclampsia and intrauterine growth retardation (IUGR), are characterized by abnormal placental development. Research by Stuart Handwerger, MD, and his colleagues examines the roles for protein hormones, transcription factors and other signaling molecules in the development of normal and pathologic placentas. They postulate that a better understanding of the factors that regulate placental growth and development may lead to the discovery of therapeutic modalities that prevent or correct abnormal placental development and that improve fetal outcome. Their recent investigations have shown that placental development is critically dependent upon the transcription factors TFAP2A and NR2F2, both of which modulate cell structure, cell growth and hormone expression. The mRNA and protein levels of both transcription factors were shown to increase markedly during placental development; silencing the expression of either transcription factor was observed to markedly inhibit development. NR2F2 and TFAP2A were shown to form a positive feedback loop in which NR2F2 induces TFAP2A expression and TFAP2A in turn induces NR2F2. NR2F2 also potentiated the effect of retinoic acid on TFAP2A. Having demonstrated that TFAP2A and NR2F2 are critical for normal placental development, Handwerger, in collaboration with Jerzy Stanek, MD, PhD, and Rachel Sheridan, MD, of the Division of Pathology, recently observed by immunohistochemical analyses  that TFAP2A protein levels in preeclampsia and IUGR placentas are markedly decreased compared to levels in gestational age-matched control placentas. Similar NR2F2 studies have not as yet been completed. Since these studies suggest that the abnormal placental development and function in preeclampsia and IUGR may be due, at least in part, to abnormalities in TFAP2A (and possibly NR2F2) expression, subsequent studies will examine whether correcting TFAP2A (and possibly NR2F2) expression in cultures of pathologic placentas will result in normal development.

Causes and Control of Type 1 Diabetes

Our research focuses on type 1 diabetes (T1D) by using a  non-obese diabetic (NOD) mouse model .  During the past year, our NIH-funded work has focused mainly on three areas:  the role plasmacytoid dendritic cells and natural killer T cells play in establishing an immunoregulatory environment in mice that are protected from disease;   the role merocytic dendritic cells play in breaking peripheral T cell tolerance to islet cell antigen (in collaboration with Edith Janssen, PhD, in the Division of Molecular Immunology); and the potential use of small molecule inhibitors of Bcl-2 family members in targeting diabetogenic CD4+ and CD8+ T cells for specific destruction to enhance long-term tolerance and to facilitate a novel therapeutic strategy to re-establish tolerance in T1D patients (in collaboration with David Hildeman, PhD, in the Division of Immunobiology).  Together these studies are designed to understand what normally controls T1D development, what underlies the basic response to beta cell antigens and, finally, what can be done to facilitate the restoration of normal beta cell function and glucose regulation in T1D patients.

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Division Publications

  1. Cunningham NR, Vesco AT, Dolan LM, Hood KK. From caregiver psychological distress to adolescent glycemic control: the mediating role of perceived burden around diabetes management. J Pediatr Psychol. 2011; 36:196-205.
  2. Dabelea D, Dolan LM, D'Agostino R, Jr., Hernandez AM, McAteer JB, Hamman RF, Mayer-Davis EJ, Marcovina S, Lawrence JM, Pihoker C, Florez JC. Association testing of TCF7L2 polymorphisms with type 2 diabetes in multi-ethnic youth. Diabetologia. 2011; 54:535-9.
  3. Ingerski LM, Anderson BJ, Dolan LM, Hood KK. Blood glucose monitoring and glycemic control in adolescence: contribution of diabetes-specific responsibility and family conflict. J Adolesc Health. 2010; 47:191-7.
  4. Katz JD, Ondr JK, Opoka RJ, Garcia Z, Janssen EM. Cutting edge: merocytic dendritic cells break T cell tolerance to beta cell antigens in nonobese diabetic mouse diabetes. J Immunol. 2010; 185:1999-2003.
  5. Kaulfers AM, Backeljauw PF, Reifschneider K, Blum S, Michaud L, Weiss M, Rose SR. Endocrine dysfunction following traumatic brain injury in children. J Pediatr. 2010; 157:894-9.
  6. Kaulfers AM, Bean JA, Inge TH, Dolan LM, Kalkwarf HJ. Bone loss in adolescents after bariatric surgery. Pediatrics. 2011; 127:e956-61.
  7. Kim HK, Gottliebson W, Hor K, Backeljauw P, Gutmark-Little I, Salisbury SR, Racadio JM, Helton-Skally K, Fleck R. Cardiovascular anomalies in Turner syndrome: spectrum, prevalence, and cardiac MRI findings in a pediatric and young adult population. AJR Am J Roentgenol. 2011; 196:454-60.
  8. Kurtulus S, Tripathi P, Moreno-Fernandez ME, Sholl A, Katz JD, Grimes HL, Hildeman DA. Bcl-2 allows effector and memory CD8+ T cells to tolerate higher expression of Bim. J Immunol. 2011; 186:5729-37.
  9. Shah AS, Dolan LM, Gao Z, Kimball TR, Urbina EM. Clustering of risk factors: a simple method of detecting cardiovascular disease in youth. Pediatrics. 2011; 127:e312-8.
  10. Shah AS, Khoury PR, Dolan LM, Ippisch HM, Urbina EM, Daniels SR, Kimball TR. The effects of obesity and type 2 diabetes mellitus on cardiac structure and function in adolescents and young adults. Diabetologia. 2011; 54:722-30.
  11. Sherafat-Kazemzadeh R, Schroeder JK, Kessler CA, Handwerger S. Parathyroid hormone-like hormone (PTHLH) represses decidualization of human uterine fibroblast cells by an autocrine/paracrine mechanism. J Clin Endocrinol Metab. 2011; 96:509-14.
  12. Slaughter JL, Meinzen-Derr J, Rose SR, Leslie ND, Chandrasekar R, Linard SM, Akinbi HT. The effects of gestational age and birth weight on false-positive newborn-screening rates. Pediatrics. 2010; 126:910-6.
  13. Urbina EM, Dolan LM, McCoy CE, Khoury PR, Daniels SR, Kimball TR. Relationship between elevated arterial stiffness and increased left ventricular mass in adolescents and young adults. J Pediatr. 2011; 158:715-21.
  14. Urbina EM, Khoury PR, McCoy C, Daniels SR, Kimball TR, Dolan LM. Cardiac and vascular consequences of pre-hypertension in youth. J Clin Hypertens (Greenwich). 2011; 13:332-42.
  15. Urbina EM, Kimball TR, Khoury PR, Daniels SR, Dolan LM. Increased arterial stiffness is found in adolescents with obesity or obesity-related type 2 diabetes mellitus. J Hypertens. 2010; 28:1692-8.
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Grants, Contracts, and Industry Agreements

Grant and Contract AwardsAnnual Direct / Project Period Direct

Dolan, L

SubClinical Cardiovascular Disease in Youth
R01 DK 07854209/22/09-08/31/11$197,323
SEARCH for Diabetes in Youth, Phase 3: Registry Study
U18 DP 00270909/30/10-09/29/15$428,578
T1D Exchange Registry
12/01/10-02/28/13$10,523
Understanding Social Status Impact on Adolescent Health
R01 HD 04152705/31/10-01/31/12$256,200

Katz, J

Dissecting Dendritic Cell Function in Autoimmune Diabetes
R01 DK 07817908/01/09-07/31/14$237,600
Dendritic Cells in the Breaking of Peripheral Tolerance in Type 1 Diabetes
R01 DK 09097809/20/10-08/31/13$185,000

Crimmins, N.

Type 1 Diabetes TrialNet
U01 DK 06105506/16/11-06/30/12$24,813

Rutter, M

DMD Insulin Growth Factor-1
11/01/10-10/31/12$254,000

Shah, A

Role of High Density Lipoprotein Subspecies in Adolescents with Type 2 Diabetes
01/26/11-06/30/11$11,140

Sisley, S

Molecular Epidemiology in Children's Environmental Health Training Program
T32 ES 01095709/01/10-06/30/11$41,530
CNS NFkappaB Regulation of Peripheral Glucose Homeostasis
11/01/10-10/31/11$20,000
Current Year Direct$1,656,184
Industry Contracts

Backeljauw, P

$7,998
$29,543
$30,025

Handwerger

$3,311

Klein

$31,801

Rose

$3,850
Current Year Direct Receipts$124,528
Total$1,780,712
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