NNRL members competed in the 26th annual NIH relay

About our work

The eye is our window to the world. The process of vision begins in the retina, and in humans, the retina supplies almost 30% of the sensory input received by the brain. Any damage to retinal neurons can have devastating consequences, including loss of vision. Retinal and macular diseases are a major cause of visual impairment and affect the quality of life of millions worldwide.

Our research seeks to answer both basic and translational questions related to the retina and especially focuses on photoreceptors which initiate the visual process. Dysfunction or loss of photoreceptors is the primary cause of vision impairment in almost all cases of retinal and macular degeneration. The primary goals of our research are to:

  1. Elucidate genetic and epigenetic control mechanisms that guide retinal development, aging and evolution
  2. Design novel therapies for retinal and macular degeneration by identifying genetic defects and cellular pathways that contribute to disease pathology

We are using state-of-the-art next generation sequencing combined with bioinformatic strategies, and developing stem cell-based approaches for gene therapy and drug discovery.

RDGT Section Updates

Current research

The following themes encompass the many projects that we are developing in our lab:

Identifying the regulatory networks that guide retinal development, homeostasis and aging

This project seeks to elucidate transcriptional and post-transcriptional regulatory networks that determine cell fate and guide the development of photoreceptors from retinal progenitor cells. We also wish to elucidate how photoreceptor function is maintained throughout life. Some of the key questions we are pursuing are:

  • What are intrinsic control mechanisms that lead to photoreceptor cell fate from retinal progenitors?
  • How are specific cell numbers and their organization with the retina determined?
  • How did nocturnality evolve?
  • Are all rods created equal?
  • Why do we have so many rod photoreceptors since cones are more useful for humans?
  • How did the fovea develop?
  • How is photoreceptor homeostasis maintained?
  • How do distinct transcriptional regulatory proteins coordinate their job with extrinsic factors and the microenvironment?
  • How does aging and environment affect gene function?
  • What is the role of the epigenome in maintaining healthy photoreceptors?
  • How do post-transcriptional events modulate the expression of functional macromolecules, including proteins and non-coding RNAs?
  • Why is splicing so prevalent in the retina?

The answers to these questions will be valuable for delineating pathogenic mechanisms that contribute to photoreceptor cell death. We previously discovered that that Maf-family bZIP transcription factor NRL is critical for rod photoreceptor fate and functional differentiation, and that loss of NRL leads to S-cones instead of rods. NRL interacts with homeodomain protein CRX and numerous other regulatory factors to control expression of most rod-expressed genes. We are now focused on delineating the transcription factors and signaling pathways that are responsible for generating photoreceptors from retinal progenitor cells. We are also interested in understanding photoreceptor morphogenesis and synapse formation. This research has been extended to include how aging affects retinal and photoreceptor function. Our investigations utilize in vivo mouse retina and human retinal organoids derived from pluripotent stem cells as study systems. We use cutting-edge genomic technologies, and focus on RNA biology and proteomics.

Evolution can provide answers to fundamental questions relating to development and function. Using a diverse sampling of species that span the full breadth of vertebrates and display all major visual ecologies, we are embarking on studies of independent evolutionary origins of traits of interest to uncover their (potentially) common molecular underpinnings. This research holds great potential for elucidating how genetic variation and regulatory elements lead to diverse visual phenotypes.

Mechanisms, modeling and therapies of retinal and macular neurodegeneration

The key translational issues that we focus on are:

  • How do inherited mutations affect photoreceptor homeostasis and cause cell death?
  • Why do some mutations manifest later in life even though the genetic change was present at birth?
  • Can we find common cellular pathways associated with photoreceptor cell death caused by distinct genetic mutations?
  • How do numerous non-coding variations in the human genome affect gene expression in the retina?
  • Do disease-associated non-coding variants primarily reside in transcriptional control elements?
  • Can we integrate aging and environmental factors through epigenomic analysis into retinal gene/protein expression?
  • What are causal genes and genetic variants associated with age-related macular degeneration?
  • How does mitochondrial function affect progression of retinal and macular disease?
  • Are mitochondrial defects an early marker of photoreceptor disease?
  • Can we target mitochondria for designing treatments?
  • Can we target multiple retinal diseases by targeting specific pathways?
  • Can we use patient-derived cells for personalized medicine?
  • Are human induced pluripotent stem cell-derived retinal organoids a good model for elucidating disease mechanisms and developing therapies?
  • How can we utilize basic science knowledge to design novel gene- or cell-based therapies of retinal and macular diseases?

Our laboratory is dedicated to identifying genetic defects that are responsible for inherited retinal degenerative diseases. Mutations in over 200 genes can result in photoreceptor degeneration. We therefore wish to elucidate disease gene networks and common cellular pathways that can be targeted for drug discovery. We collaborate with clinicians and scientists worldwide for disease gene discovery and use mouse models and/or human patient stem cell-derived retinal organoids for modeling Retinitis Pigmentosa and/or Leber's congenital amaurosis. Our current focus is on developing treatments for retinal diseases caused by mutations in CEP290, CRX, NPHP5, RPGR and RP2.

Our lab is identifying susceptibility variants associated with age-related macular degeneration (AMD), a multifactorial blinding disease affecting the elderly. Our current focus is on delineating causal genes and genetic variants that contribute to AMD pathology. We are defining regulatory elements/factors that control gene expression in the human retina, and integrating these with epigenetic and post-transcriptional regulation.

Jobs, fellowships, and internships

Postdoctoral fellowships in development, evolution and neurodegeneration

We are looking for outstanding candidates with a PhD or MD/PhD in any area of cell or developmental biology, genetics, biochemistry or computational sciences to pursue innovative studies using retina and/or stem cells as a model system. Successful candidates will display an excellent publication record, a strong passion to conduct independent scientific research, and possess excellent communication and interpersonal skills. Annual stipend will be commensurate with experience and training.

Interested applicants should submit a cover letter with career goals, potential research projects of interest, curriculum vitae with publications, and contact information of three references to Dr. Anand Swaroop at swaroopa@nih.gov.

The National Institutes of Health is dedicated to building a diverse community in its training and employment programs. The Department of Health and Human Services, National Institutes of Health, and the National Eye Institute are equal opportunity employers.

Internships

Not currently available.

Selected publications

2019

SSBP1 faux pas in mitonuclear tango causes optic neuropathy. J. Clin. Invest. DOI:10.1172/JCI132532.

Improved retinal organoid differentiation by modulating signaling pathways revealed by comparative transcriptome analyses with development in vivo. Stem Cell Reports. PMID:31631019.

Transcriptome-based molecular staging of human stem cell-derived retinal organoids uncovers accelerated photoreceptor differentiation by 9-cis retinal. Mol. Vision. Available here.

Retinal disease in ciliopathies: Recent advances with a focus on stem cell-based therapies. Translational Science of Rare Diseases. DOI:10.3233/TRD-190038.

Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration. JAMA Ophthalmol. PMID:31120506.

Age-related changes of the retinal microvasculature. PLoS One. PMID:31048908.

The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies. Acta Ophthalmol. PMID:30925032.

Retinal Transcriptome and eQTL Analyses Identify Genes Associated with Age-Related Macular Degeneration. Nature Genet. PMID:30742112.

Association of Age-Related Macular Degeneration with Complement Activation Products, Smoking, and Single Nucleotide Polymorphisms in South Carolinians of European and African Descent. Mol. Vision. PMID:30820144.

2018

Mitochondrial Respiration in Outer Retina Contributes to Light-Evoked Increase in Hydration In Vivo. Invest. Ophthalmol. Vis. Sci. PMID:30551203.

Targeted Deletion of an NRL- and CRX-regulated Alternative Promoter Specifically Silences FERM and PDZ Domain Containing 1 (Frmpd1) in Rod Photoreceptors. Human Mol. Genetic. PMID:30445545.

A CEP290 C-Terminal Domain Complements the Mutant CEP290 of Rd16 Mice In Trans and Rescues Retinal Degeneration. Cell Reports. PMID:30332642.

Mini and Customized Low-Cost Bioreactors for Optimized High-Throughput Generation of Tissue Organoids. Stem Cell Investigation. PMID:30498744.

Molecular Dissection of Cone Photoreceptor‐enriched Genes Encoding Transmembrane and Secretory Proteins. J. Neurosci. Res. PMID:30260491.

Cone-rod Homeobox CRX Controls Presynaptic Active Zone Formation in Photoreceptors of Mammalian Retina. Human Mol. Genetic. PMID:30084954.

Patient iPSC-derived Neural Stem Cells exhibit Phenotypes in Concordance with the Clinical Severity of Mucopolysaccharidosis I. Human Mol. Genet. PMID:30052969.

Postnatal Developmental Dynamics of Cell Type Specification Genes in Brn3a/Pou4f1 Retinal Ganglion Cells. Neural Dev. 2018;13(1):15. PMID:29958540.

Epigenetic Control of Gene Regulation during Development and Disease: A View from the Retina. Prog Retin Eye Res. 2018:S1350-9462(17)30104-0. PMID:29544768.

RNA Biology in Retinal Development and Disease. Trends Genet. 2018;34(5):341-351. PMID:29395379.

Genome-wide Analysis of Disease Progression in Age-related Macular Degeneration. Hum Mol Genet. 2018;27(5):929-940. PMID:29346644.

Accelerated and Improved Differentiation of Retinal Organoids from Pluripotent Stem Cells in Rotating-Wall Vessel Bioreactors. Stem Cell Reports. 2018;10(1):300-313. PMID:29233554.

2017

Accelerated and Improved Differentiation of Retinal Organoids from Pluripotent Stem Cells in Rotating-Wall Vessel Bioreactors. Stem Cell Reports. 2018;10(1):300-313. PMID:29233554.

Molecular Anatomy of the Developing Human Retina. Dev Cell. 2017;43(6):763-779. PMID:292334770.

In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations. Cell Rep. 2017;20(2):384-396. PMID:28700940.

Pias3 is necessary for dorso-ventral patterning and visual response of retinal cones but is not required for rod photoreceptor differentiation. Biol Open. 2017;6(6):881-890. PMID:28495965.

REEP6 mediates trafficking of a subset of Clathrin-coated vesicles and is critical for rod photoreceptor function and survival. Hum Mol Genet. 2017;26(12):2218-2230. PMID:28369466.

Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice. Nat Commun. 2017;8:14716. PMID:28291770.

2016

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors. Cell Rep. 2016;17(9):2460–2473. PMID:27880916.

Recruitment of Rod Photoreceptors from Short-Wavelength-Sensitive Cones during the Evolution of Nocturnal Vision in Mammals. Dev Cell. 2016;37(6):520-32. PMID:27326930.

Next generation sequencing technology and genomewide data analysis: Perspectives for retinal research. Prog Retin Eye Res. 2016;55:1-31. PMID:27297499.

Centrosomal protein CP110 controls maturation of the mother centriole during cilia biogenesis. Development. 2016;143(9):1491-501. PMID:26965371.

2015

Quantification of Oxygen Consumption in Retina Ex Vivo Demonstrates Limited Reserve Capacity of Photoreceptor Mitochondria. Invest Ophthalmol Vis Sci. 2015;56(13):8428-36. PMID:26747773.

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 201648(2):134-43. PMID:26691988.

Transcriptome Dynamics of Developing Photoreceptors in Three-Dimensional Retina Cultures Recapitulates Temporal Sequence of Human Cone and Rod Differentiation Revealing Cell Surface Markers and Gene Networks. Stem Cells. 2015;33(12):3504–3518. PMID:26235913.

2014

Ciliopathy-associated gene Cc2d2a promotes assembly of subdistal appendages on the mother centriole during cilia biogenesis. Nat Commun. 2014;5:4207. PMID:24947469.

Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. Hum Mol Genet. 2014;23(21): 5827–5837. PMID:24899048.

Age-Related Macular Degeneration: Genetics and Biology Coming Together. Annu Rev Genomics Hum Genet. 2014;15:151–171. PMID:24773320.

Regulation of a novel isoform of Receptor Expression Enhancing Protein REEP6 in rod photoreceptors by bZIP transcription factor NRL. Hum Mol Genet. 2014; 23(16): 4260–4271. PMID:24691551.

The transcription-splicing protein NonO/p54nrb and three NonO-interacting proteins bind to distal enhancer region and augment rhodopsin expression. Hum Mol Genet. 2014;23(8):2132-44. PMID:24301678.

Ancestry estimation and control of population stratification for sequence-based association studies. Nat Genet. 2014;46(4):409-15. PMID:24633160.

Retinal Development, Genetics and Therapy Section key staff

Key staff table
Name Title Email Phone
Anand Swaroop, Ph.D. Senior Investigator swaroopa@nei.nih.gov 301-435-5754
Andrew Smith, Ph.D. Postdoctoral Fellow andrew.smith3@nih.gov 301-827-6098
Anupam Mondal, Ph.D. Postdoctoral Fellow anupam.mondal@nih.gov 301-443-5132
Benjamin Fadl, B.S. Graduate Student benjamin.fadl@nih.gov 301-827-4216
Catherine Jaeger, Ph.D. Postdoctoral Fellow catherine.jaeger@nih.gov 301-827-6095
Claire Marchal, Ph.D. Postdoctoral Fellow claire.marchal@nih.gov 301-443-5132
Coco (Ke) Jiang, Ph.D. Postdoctoral Fellow coco.jiang@nih.gov 301-443-5169
Holly Chen, Ph.D. Research Fellow holly.chen@nih.gov 301-443-7820
James Gentry, B.S. Postbaccalaureate Student james.gentry@nih.gov 301-451-6439
Jayshree Advani, Ph.D. Postdoctoral Fellow jayshree.advani@nih.gov 301-443-7406
Koray Kaya, Ph.D. Research Fellow koraydogan.kaya@nih.gov 301-827-4815
Laura Campello, Ph.D. Postdoctoral Fellow laura.campello@nih.gov 301-827-6093
Lina Zelinger, Ph.D. Postdoctoral Fellow lina.zelinger@nih.gov 301-451-6440
Michael Phelan, B.S. Graduate Student michael.phelan2@nih.gov 301-443-5132
Michael Power, Ph.D. Postdoctoral Fellow michael.power@nih.gov 301-443-5791
Mrinal Dewanjee, Ph.D. Special Volunteer mrinal.dewanjee@nih.gov 301-443-0416
Nivedita Singh, Ph.D. Postdoctoral Fellow nivedita.singh@nih.gov 301-443-7406
Noor White, Ph.D. Postdoctoral Fellow noor.white@nih.gov 301-402-5734
Partha Dey, Ph.D. Postdoctoral Fellow deypn@nei.nih.gov 301-402-5755
Ryan Strickland, B.S. Postbaccalaureate Student ryan.strickland@nih.gov 301-443-5791
Samantha Papal, Ph.D. Research Fellow samantha.papal@nih.gov 301-443-5791
Scott Henke, Ph.D. Postdoctoral Fellow scott.henke@nih.gov 301-443-2917
Ximena Corso-Díaz, Ph.D. Postdoctoral Fellow ximena.corsodiaz@nih.gov 301-451-6439
Xulong Liang, Ph.D. Postdoctoral Fellow liangx6@nih.gov 301-443-7399
Last updated: December 2, 2019