OMB No. 0925-0001 and 0925-0002 (Rev. 03/2020 Approved Through 02/28/2023)

NAME: Linda Leatherbury

eRA COMMONS USER NAME (credential, e.g., agency login): lleather

POSITION TITLE: Pediatric Cardiologist

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

1. Personal Statement:

I am a pediatric cardiologist and basic researcher with a longstanding interest in using model systems (mouse and chicken) to elucidate the developmental mechanisms leading to congenital malformations of the heart. My role in this project will be to assist with the analysis of cardiac phenotypes in Hectd1 mutant embryos and provide general guidance on analysis of mouse models with CHDs.  I have years of experience engaged in  productive collaborations with basic researchers in this realm.  During the 15 years I was an Assistant and then Associate professor at the Medical College of Georgia, I worked with Dr. Margaret Kirby’s Heart Development Group at the Medical College of Georgia where I made substantial contributions to our knowledge of defects in neural crest ablated chick embryos, a model of DiGeorge Syndrome (22q11 deletions syndromes). Since returning to Children’s in 2001, I established a productive long-term collaboration with Cecilia W. Lo, PhD. at the NHLBI.  In addition, to directing the clinical research at Children’s National assessing ciliary dysfunction in heterotaxy and other congenital heart disease patients, as an investigator in the Bench to Bassinet CvDC program, I investigate the genetic basis of congenital heart defects in mice.  Over the past decade, I developed the phenotypic analysis of fetal mice in a forward recessive screen from a chemical mutagen (ENU). I was the senior researcher for echocardiographic, EFIC (microscopic MRI) and web data site phenotyping in collaboration with Dr. Cecilia Lo while at NHLBI, NIH. At NIH with Dr. Lo, we characterized a mutant Dnahc5 (DNAH5) mouse with heterotaxy complex congenital heart defects and airway ciliary dysfunction that lead to a DOD grant in humans with complex congenital heart disease and ciliary dysfunction. I worked with NHLBI and NHGRI intramural investigators phenotyping mutant mouse lines with adult and fetal echocardiography in the NIH Mouse Imaging Facility and utilizing fetal ultrasound imaging to enable gene therapy in embryonic mice whose mutant line develops metabolic cardiomyopathy. More recently, I developed a similar embryonic or fetal mouse echocardiographic imaging program at Children’s National Research Institute where I was a professor of Pediatrics in the Center for Genetics. Our first manuscript is published below in 2021. Throughout my professional career, I was a clinical pediatric cardiologist seeing patients and their families for the Cardiology department of Children’s National Hospital. I am now an emeritus professor of pediatrics for George Washington Medical School and Health Sciences University.

Most relevant publications to this proposal.

1. Yelbuz TM, Waldo KL, Kumiski HT, Stadt HTL, Wolfe RR, Leatherbury L, Kirby ML. 2002. Shortened Outflow Tract Leads to Altered Cardiac Looping after Neural Crest Ablation. Circulation. 106(4) 504-510. PMID:12135953.

2. Yu Q, Shen Y, Chatterjee B, Siegfried BH, Leatherbury L, Rosenthal J, Lucas JF, Wessels A, Spurney CF, Wu YJ, Kirby ML, Svenson K, Lo CW.  2004.  ENU Induced Mutations Causing Congenital Cardiovascular Anomalies.  Development. 131(24):6211-6223. PMID:15548583

3. Sugrue KF, Sarkar AA, Leatherbury L, Zohn IE. (2019) The Ubiquitin Ligase Hectd1 Promotes Retinoic Acid Signaling Required for Development of the Aortic Arch. Dis Model Mech. Jan 11;12(1). pii: dmm036491, PMCID: PMC6361158

4. Mokshagundam D,  Garcia-Pak, I, Klaunberg B, Kowalski W, Nam J, Mukouyama Y, Leatherbury L: (2021) Ultra-high frequency echocardiography of Autonomic Devoid Phox2B Homozygous Embryos Does Not Reveal a Significant Cardiac Phenotype before Embryo Death. Ultrasound in Med  Biol. 2021 Mar;47(3):751-758 PMID: 33293111

5. Romanowicz J, Guerrelli D, Dhari Z, Mulvany C, Reilly M, Swift L, Vasandani, Ramadan M, Leatherbury L, Ishibashi N, Posnack NG. (2021) Chronic Prenatal Hypoxia Delays Cardiac Maturation in a Mouse Model for Cyanotic Congenital Heart Disease. Am J Physiol. Heart Circ Physiol Mar 19, 2021; H1873-H1886

6. Sugrue KF Yitsege G, Romanowicz J, Oluwo O, Leatherbury L, Zohn IE. (Under Revision) HECTD1 is Required for Growth of the Myocardium Secondary to Placental Insufficiency. Dev. Biol. DEVELOPMENTALBIOLOGY_2018_576

B.     Positions and Honors

Positions and Employment

1978 – 1981        Pediatric Resident, Children’s Hospital National Medical Center, Washington, DC

1981 – 1985        Pediatric Cardiology Fellowship, Children’s Hospital National Medical Center, Washington, DC

1981 – 1985        Clinical Instructor of Pediatrics, Children’s Hospital National Medical Center, Washington, DC

1985 – 1990        Assistant Professor of Pediatrics, Section of Pediatric Cardiology, Medical College of Georgia, Augusta, GA

1985 – 2000        Director of Pediatric Cardiac Catheterization Laboratory Medical College of Georgia, Augusta, GA

1986 – 2001        Director of the Cardiac Catheterization Blood Gas Laboratory, Medical College of Georgia, Augusta, GA

1988 – 2001        American Academy of Pediatrics Representative to the American College of Cardiology

1990 – 1997        Associate Professor of Pediatrics, Section of Pediatric Cardiology, Medical College of Georgia

1996 – 1997        Associate Professor of Developmental Biology Program, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA

1997 – 2001        Professor of Pediatrics, Section of Pediatric Cardiology, Developmental Biology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA

2000 – 2001        Professor of Pediatrics, Section of Pediatric Cardiology, Children’s Medical College of Georgia, Augusta, GA

2001 – 2024         Pediatric Cardiologist, Center for Heart, Lung and Kidney, Children’s National Medical Center, Washington, DC

2001 –2023         Physician Scientist, Developmental Biology, National Heart, Lung and Blood Institute, National Institutes of Health

2002 – 2024        Professor of Pediatrics, The George Washington School of Medicine and Health Sciences, Cardiology and the Center for Genetics at Children’s Research Institute at the Children’s National Medical Center, Washington, DC

2022 – 2024        Emeritus Professor of Pediatrics, The George Washington School of Medicine and Health Sciences, Cardiology and the Center for Genetics at Children’s Research Institute at the Children’s National Medical Center, Washington, DC

Honors and Awards

1973    Phi Beta Kappa

1977    Alpha Omega Alpha

1978    American Medical Women’s Association Scholastic Achievement Award

1981    The Dr. Maynard L. Cohen Memorial Award for Outstanding Pediatric Resident

1995    The Society for Pediatric Research

2008    The American Pediatric Society

2008. CNMC Faculty Research Award, Honorable Mention

Press Ganey Award; Virtual Recognition Wall

2. Contributions to Science (Total number of publications is 48 - https://www.ncbi.nlm.nih.gov/pubmed)
    

1. Established the neural crest ablated chick as a model of DiGeorge Syndrome.  While working with Dr. Kirby, I made significant contributions to our current understanding of the contribution of the neural crest to development of the outflow tract.

1. Leatherbury L, Gauldin HE, Waldo K, Kirby ML.  1990.  Microcinephotography of the Developing Heart in Neural Crest-Ablated Chick Embryos.  Circulation 81:1047-1057. PMID:2306815

2. Leatherbury L, Connuck DM, Gauldin HE, Kirby ML. 1991.  Hemodynamic Changes and Compensatory Mechanisms During Early Cardiogenesis Following Neural Crest Ablation in Chick Embryos.  Pediatric Research 30(6):509-512, PMID:1805144

3. Leatherbury L, Connuck DM, Kirby ML. 1993. Neural Crest Ablation versus Sham Surgical effects in a Chick Embryo Model of Defective Cardiovascular Development.  Pediatric Research 33(6):628-631,. PMID:8378123

4. Leatherbury L, Waldo K. 1995.  Visual Understanding of Cardiac Development: The Neural Crest’s Contribution.  Cellular and Molecular Biology Research, 41(4):279-291, PMID:8775985

2. Established ciliary dysfunction as a major cause of congenital heart defects. Through a productive long term collaboration with Cecilia W. Lo, at NIHLB, I directed research at Children’s National assessing ciliary dysfunction in heterotaxy and other congenital heart disease patients with a landmark study showing increased ciliary dysfunction in heterotaxy patients.

1. Aune CN, Chatterjee B, Zhao XQ, Francis R, Bracero L, Yu Q, Rosenthal J, Leatherbury L, Lo CW.  2008.  Mouse Model of Heterotaxy Syndrome with Single Ventricle Spectrum of Cardiac Anomalies. Pediatr Res 63(1) 9-14. PMID:18043505

2. Tan S, Rosenthal J, Zhao X, Francis R, Chatterjee B, Sabol SL, Linask  KL, Bracero L, Connelly P, Daniels P, Qing Yu Q, Omran H, Leatherbury L, and Lo CW. 2007. Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia. J. Clin. Invest. 117(12) 3742-3752. PMCID: PMC2082149

3. Frank L, Yu Q, Francis R, Samtani R; Sahn D, Leatherbury L, Lo C.W. 2010 Ventricular rotation is independent of cardiac looping: a study in mice with situs inversus totalis using speckle-tracking echocardiography. J Am Soc of Echocardiogr 23(3) 315-23. PMID:20097527

4. Adams PS, Tian X, Zahid M, Khalifa O, Leatherbury L, Lo CW. 2015. Establishing normative nasal nitric oxide values in infants. Respir Med. 2015 Sep;109(9):1126-30. PMID:26233707.

3. Investigated the genetic basis of congenital heart defects in mice. As part of the Bench to Bassinet CvDC grant, I developed the phenotypic analysis of fetal mice in a forward recessive screen from a chemical mutagen (ENU). I am the senior researcher for echocardiographic, EFIC (microscopic MRI) and web data site phenotyping in collaboration with Dr. Cecilia Lo. I also described a mutant Dnahc5 (DNAH5) mouse family with heterotaxy complex congenital heart defects and airway ciliary dysfunction. 

1. Kim A, Francis F, Liu X, Devine W, Ramirez R, Anderton S, Wong L, Faruque F, Gabriel G, Leatherbury L, Tobita K, Lo CW. 2013. Microcomputed tomography provides high accuracy congenital heart disease diagnosis in neonatal and fetal mice. Circ Cardiovasc Imaging. 6(4):551-9. PMCID: PMC3908688

2. Li Y, Klena NT, Gabriel GC, Liu X, Kim AJ, Lemke K, Chen Y, Chatterjee B, Devine W, Damerla RR, Chang C, Yagi H, San Agustin JT, Thahir M, Anderton S, Lawhead C, Vescovi A, Pratt H, Morgan J, Haynes L, Smith CL, Eppig JT, Reinholdt L, Francis R, Leatherbury L, Ganapathiraju MK, Tobita K, Pazour GJ, Lo CW. 2015. Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature. 521(7553):520-4. PMCID: PMC4617540

3. Liu X, Yagi H, Saeed S, Bais AS, Gabriel GC, Chen Z, Peterson KA, Li Y, Schwartz MC, Reynolds WT, Saydmohammed M, Gibbs B, Wu Y, Devine W, Chatterjee B, Klena NT, Kostka D, de Mesy Bentley KL, Ganapathiraju MK, Dexheimer P, Leatherbury L, Khalifa O, Bhagat A, Zahid M, Pu W, Watkins S, Grossfeld P, Murray SA, Porter GA Jr, Tsang M, Martin LJ, Benson DW, Aronow BJ, Lo CW. 2017. The complex genetics of hypoplastic left heart syndrome. Nat Genet. 49(7):1152-1159. PMCID: PMC5737968

4. Leatherbury L, Berul CI. 2017. Genetics of Congenital Heart Disease: Is the Glass Now Half-Full? Circ Cardiovasc Genet. 10(3):e001746. PMID: 28468791

4. Investigated the impact of ciliary dysfunction on congenital heart defects in humans. I conducted a protocol at CNMC showing that human patients with heterotaxy congenital heart defects had a high prevalence of ciliary dysfunction. and conducted clinical studies in infants and children showing that heterotaxy post-operative patients have increased mortality and respiratory complications, particularly those with ciliary dysfunction. In collaboration with Dr. Lo at the University of Pittsburgh, we have also seen ciliary dysfunction in non-heterotaxy congenital heart defect patients. I see these clinical translational studies as the real gems showing how basic research can impact clinical care.

1. Swisher M, Jonas R, Tian X, Lo CW, Leatherbury L. 2010. Increased postoperative and respiratory complications in patients with congenital heart disease associated with heterotaxy. J Thorac and Cardiovasc Surg. 141(3):637-44. PMCID: PMC3021800

2. Nakhleh N, Francis R, Giese R , Tian X, Li Y, Zariwala M, Yagi H, Khalifa O, Kureshi S; Chatterjee B, Sabol S, Swisher M, Connelly P, Daniels M, Srinivasan A, Sami I, Kuehl K,  Kravitz N, Burns K, Sami I, Omran H, Barmada M, Olivier K , Chawla K, Leigh M, Knowles M, Jonas R, Leatherbury L, Lo C. 2012. High  Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients with Heterotaxy. Circulation. 125(18) 2232-2242. PMCID: PMC3770728

3. Harden B, Tian X, Giese R, Nakhleh N, Kureshi S,  Francis R, Hanumanthaiah S,  Li Y, Swisher M, Kuehl K, Sami I, Olivier K, Jonas J, Lo CW, Leatherbury L. 2014. Increased Postoperative Respiratory Complications in Heterotaxy Congenital Heart Disease Patients With Respiratory Ciliary Dysfunction. J Thorac Cardiovasc Surg.  147(4):1291-1298. PMCID: PMC3021800

4. Adams PS, Tian X, Zahid M, Khalifa O, Leatherbury L, Lo CW. Establishing normative nasal nitric oxide values in infants. Respir Med. 2015 Sep;109(9):1126-30. PMID:26233707

D.        Additional Information: Research Support

Recent Completed Research Support

R01HL132024 (Lo)                                                                                                     Role: Co-Investigator                                 4/2016 - 3/2020

Title: Modeling the complex genetics of congenital heart disease in mice.

The goal of this project is to conduct a sensitized screen for the systematic interrogation of the mouse genome for semi-dominant CHD mutations

DOD # PR140183 (Lo and Leatherbury)                               Role: Co-PI                                                              9/2015–10/2019

Title: Respiratory Ciliary Dysfunction and Pulmonary Risks in Congenital Heart Disease

The goal of this project is to test the hypothesis that respiratory ciliary dysfunction in CHD patients impairs lung function and leads to increased post-surgical respiratory complications and worse outcomes.

R01GM104412 (PI: Cecila Lo)                                                           Role: Co-Investigator                                         09/2014 – 08/2018

Assaying heterotaxy patient genes in cilia motility and left-right patterning.

The goal of this project was to develop functional assays and software to assess cilia candidate genes containing rare coding variants identified in heterotaxy patients for their role in airway cilia motility and left-right patterning of organ asymmetries.

Z01HL005701 (PI: Cecila Lo)                                                                         Role: Co-Investigator                                   09/2014 – 08/2018

Cell and molecular basis for congenital heart disease.

The goal of this project was to develop functional assays and software to assess cilia candidate genes containing rare coding variants identified in heterotaxy patients for their role in airway cilia motility and left-right patterning of organ asymmetries.

5U01HL098180 (PI: Cecila Lo)                                                                      Role: Co-Investigator                                   09/2009 – 07/2015

Modeling the genetic basis for human congenital heart disease in mice

The goal of this project was to perform a forward genetic screening with ethylnitrosourea mutagenesis to recover mutations causing CHD use noninvasive fetal echocardiography.

M01RR020359, subproject 6443 (PI: Leatherbury)                     Role: PI                                                         01/2008 – 11/2010

Ciliary dysfunction as an underlying etiology linking primary ciliary dyskensa.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this study is to elucidate the possible role of primary ciliary dyskinesia (PCD) in complex congenital heart disease associated with heterotaxy.

5P01HL036059, subproject 0003 (Leatherbury)                                            Role: PI                                                                                 1991-1993

Hemodynamics of heart development