Dr. Jen Ikle completed a combined MD/PhD program at the University of Colorado Denver, Anschutz Medical campus. While earning her PhD, she worked in the lab of Dr. David Clouthier studying genetics and transcriptional regulatory networks, with an emphasis on craniofacial development in the embryo. After completion of her MD, Jen completed both Pediatrics Residency and Fellowship in Pediatric Endocrinology and Diabetes at Washington University in St. Louis and St. Louis Children’s Hospital. During her fellowship, Jen worked in the lab of Dr. Colin Nichols where she developed a passion for regulation of insulin secretion from the beta cells of the pancreas. She has a specific interest in the role of ATP-sensitive potassium (KATP) channels. Genetic disruption of these channels leads to neonatal diabetes (in KATP gain of function mutations) or congenital hyperinsulinism (in KATP loss of function mutations). Jen also has a clinical interest in diabetes and hyperinsulinism.
Instructor, Pediatrics - Endocrinology and Diabetes
Boards, Advisory Committees, Professional Organizations
Member, American Diabetes Association (2020 - Present)
Member, Pediatric Endocrine Society (2017 - Present)
Member, American Academy of Pediatrics (2013 - Present)
Fellowship: St Louis Children's Hospital Washington University (2020) MO
Board Certification: American Board of Pediatrics, Pediatrics (2017)
Residency: St Louis Children's Hospital Washington University Pediatric Residency (2017) MO
Medical Education: University of Colorado School of Medicine (2014) CO
Fellowship, Washington University and St. Louis Children's Hospital, Pediatric Endocrinology and Diabetes (2020)
Board Certification, American Board of Pediatrics, General Pediatrics (2017)
Residency, Washington University and St. Louis Children's Hospital, Pediatrics (2017)
Internship, Washington University and St. Louis Children's Hospital, Pediatrics (2015)
Ph.D., University of Colorado Denver, Cells, Stem Cells, and Developmental Biology (2012)
M.D., University of Colorado Denver (2014)
Current Research and Scholarly Interests
Jen is interested in the genetic factors that lead to abnormal beta-cell function and insulin secretion, causing disorders such as hyperinsulinism and neonatal diabetes. Jen’s current research focus is the use of zebrafish models, combined with genetics and genomics, to understand cellular and molecular mechanisms of glucose metabolism and elucidate previously unknown players involved in the regulation of insulin secretion.
Neonatal Hypoglycemia: Progress and Predicaments
JOURNAL OF PEDIATRICS
2021; 235: 82
View details for Web of Science ID 000676575200020
A brief history of diabetes genetics: insights for pancreatic beta-cell development and function.
The Journal of endocrinology
Since the discovery of insulin 100 years ago, our knowledge and understanding of diabetes has grown exponentially. Specifically, with regards to the genetics underlying diabetes risk, our discoveries have paralleled developments in our understanding of the human genome and our ability to study genomics at scale; these advancements in genetics have both accompanied and led to those in diabetes treatment. This review will explore the timeline and history of gene discovery and how this has coincided with progress in the fields of genomics. Examples of genetic causes of monogenic diabetes are presented and the continuing expansion of allelic series in these genes and the challenges these now cause for diagnostic interpretation along with opportunities for patient stratification are discussed.
View details for DOI 10.1530/JOE-21-0067
View details for PubMedID 34196608
Progress in Pediatric Diabetes Prediction, Management, and Outcomes
JOURNAL OF PEDIATRICS
2021; 233: 131
View details for Web of Science ID 000655264900025
Beta-cell excitability and excitability-driven diabetes in adult Zebrafish islets.
2019; 7 (11): e14101
Islet β-cell membrane excitability is a well-established regulator of mammalian insulin secretion, and defects in β-cell excitability are linked to multiple forms of diabetes. Evolutionary conservation of islet excitability in lower organisms is largely unexplored. Here we show that adult zebrafish islet calcium levels rise in response to elevated extracellular [glucose], with similar concentration-response relationship to mammalian β-cells. However, zebrafish islet calcium transients are nor well coupled, with a shallower glucose-dependence of cytoplasmic calcium concentration. We have also generated transgenic zebrafish that conditionally express gain-of-function mutations in ATP-sensitive K+ channels (KATP -GOF) in β-cells. Following induction, these fish become profoundly diabetic, paralleling features of mammalian diabetes resulting from equivalent mutations. KATP -GOF fish become severely hyperglycemic, with slowed growth, and their islets lose glucose-induced calcium responses. These results indicate that, although lacking tight cell-cell coupling of intracellular Ca2+ , adult zebrafish islets recapitulate similar excitability-driven β-cell glucose responsiveness to those in mammals, and exhibit profound susceptibility to diabetes as a result of inexcitability. While illustrating evolutionary conservation of islet excitability in lower vertebrates, these results also provide important validation of zebrafish as a suitable animal model in which to identify modulators of islet excitability and diabetes.
View details for DOI 10.14814/phy2.14101
View details for PubMedID 31161721
View details for PubMedCentralID PMC6546968
Nkx2.5 regulates endothelin converting enzyme-1 during pharyngeal arch patterning.
Genesis (New York, N.Y. : 2000)
2017; 55 (3)
In gnathostomes, dorsoventral (D-V) patterning of neural crest cells (NCC) within the pharyngeal arches is crucial for the development of hinged jaws. One of the key signals that mediate this process is Endothelin-1 (EDN1). Loss of EDN1 binding to the Endothelin-A receptor (EDNRA) results in loss of EDNRA signaling and subsequent facial birth defects in humans, mice and zebrafish. A rate-limiting step in this crucial signaling pathway is the conversion of immature EDN1 into a mature active form by Endothelin converting enzyme-1 (ECE1). However, surprisingly little is known about how Ece1 transcription is induced or regulated. We show here that Nkx2.5 is required for proper craniofacial development in zebrafish and acts in part by upregulating ece1 expression. Disruption of nkx2.5 in zebrafish embryos results in defects in both ventral and dorsal pharyngeal arch-derived elements, with changes in ventral arch gene expression consistent with a disruption in Ednra signaling. ece1 mRNA rescues the nkx2.5 morphant phenotype, indicating that Nkx2.5 functions through modulating Ece1 expression or function. These studies illustrate a new function for Nkx2.5 in embryonic development and provide new avenues with which to pursue potential mechanisms underlying human facial disorders.
View details for DOI 10.1002/dvg.23021
View details for PubMedID 28109039
View details for PubMedCentralID PMC5364067
Identification and characterization of the zebrafish pharyngeal arch-specific enhancer for the basic helix-loop-helix transcription factor Hand2.
2012; 368 (1): 118–26
The development of the vertebrate jaw relies on a network of transcription factors that patterns the dorsal-ventral axis of the pharyngeal arches. Recent findings in both mouse and zebrafish illustrate that the basic-helix-loop-helix transcription factor, Hand2, is crucial in this patterning process. While Hand2 has functionally similar roles in these two species, little is known about the regulatory sequences controlling hand2 expression in zebrafish. Using bioinformatics and Tol2-mediated transgenesis, we have generated zebrafish transgenic reporter lines in which either the mouse or zebrafish arch-specific hand2 enhancer direct expression of a fluorescent reporter. We find that both the mouse and zebrafish enhancers drive early reporter expression in a hand2-specific pattern in the ventral pharyngeal arches of zebrafish embryos. These lines provide useful tools to follow ventral arch cells during vertebrate jaw development while also allowing dissection of hand2 transcriptional regulation during this process.
View details for DOI 10.1016/j.ydbio.2012.05.003
View details for PubMedID 22595513
View details for PubMedCentralID PMC3676283
- Nkx2.5 regulates hand2 expression in the zebrafish pharyngeal arches via a conserved enhancer ACADEMIC PRESS INC ELSEVIER SCIENCE. 2011: 233
- Transcriptional regulation of hand2 in zebrafish neural crest cells and cardiomyocytes ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: 460
Pathogen entrapment by transglutaminase--a conserved early innate immune mechanism.
2010; 6 (2): e1000763
Clotting systems are required in almost all animals to prevent loss of body fluids after injury. Here, we show that despite the risks associated with its systemic activation, clotting is a hitherto little appreciated branch of the immune system. We compared clotting of human blood and insect hemolymph to study the best-conserved component of clotting systems, namely the Drosophila enzyme transglutaminase and its vertebrate homologue Factor XIIIa. Using labelled artificial substrates we observe that transglutaminase activity from both Drosophila hemolymph and human blood accumulates on microbial surfaces, leading to their sequestration into the clot. Using both a human and a natural insect pathogen we provide functional proof for an immune function for transglutaminase (TG). Drosophila larvae with reduced TG levels show increased mortality after septic injury. The same larvae are also more susceptible to a natural infection involving entomopathogenic nematodes and their symbiotic bacteria while neither phagocytosis, phenoloxidase or-as previously shown-the Toll or imd pathway contribute to immunity. These results firmly establish the hemolymph/blood clot as an important effector of early innate immunity, which helps to prevent septic infections. These findings will help to guide further strategies to reduce the damaging effects of clotting and enhance its beneficial contribution to immune reactions.
View details for DOI 10.1371/journal.ppat.1000763
View details for PubMedID 20169185
View details for PubMedCentralID PMC2820530
Cardiac expression of the Drosophila Transglutaminase (CG7356) gene is directly controlled by myocyte enhancer factor-2.
Developmental dynamics : an official publication of the American Association of Anatomists
2008; 237 (8): 2090–99
The myocyte enhancer factor-2 (MEF2) family of transcription factors plays key roles in the activation of muscle structural genes. In Drosophila, MEF2 accumulates at high levels in the embryonic muscles, where it activates target genes throughout the mesoderm. Here, we identify the Transglutaminase gene (Tg; CG7356) as a direct transcriptional target of MEF2 in the cardiac musculature. Tg is expressed in cells forming the inflow tracts of the dorsal vessel, and we identify the enhancer responsible for this expression. The enhancer contains three binding sites for MEF2, and can be activated by MEF2 in tissue culture and in vivo. Moreover, loss of MEF2 function, or removal of the MEF2 binding sites from the enhancer, results in loss of Tg expression. These studies identify a new MEF2 target in the cardiac musculature. These studies provide a possible mechanism for the activation of transglutaminase genes.
View details for DOI 10.1002/dvdy.21624
View details for PubMedID 18627097
View details for PubMedCentralID PMC2542504