Hetian Lei, Ph.D.

Harvard Medical School

Assistant Professor of Ophthalmology

Schepens Eye Research Institute of Massachusetts Eye and Ear

Assistant Scientist

Research Summary

Center/Research Area Affiliations

Biography

Dr. Lei's research aims to prevent and cure blinding eye diseases by elucidating their molecular bases, identifying potential therapeutic targets, and demonstrating whether the targets can be used for therapeutic purposes. VEGF plays a central role in angiogenesis— new blood vessel growth from pre-existing vasculature—and its receptor VEGFR2 mediates almost all known VEGF-induced output, including neovascularization. The inhibition of VEGF-stimulated activation of VEGFR2 has become important therapy to treat abnormal angiogenesis associated with proliferative diabetic retinopathy (PDR) and neovascular age-related macular degeneration (AMD). Dr. Lei's current research explores a novel therapeutic approach to PDR and AMD with an AAV-CRISPR/Cas9-based gene therapy.

Dr. Lei also investigates the molecular mechanisms by which platelet-derived growth factor receptor (PDGFR) promotes experimental proliferative vitreoretinopathy (PVR). His research demonstrated that non-PDGFs in the vitreous engage their own receptors and thereby increase the level of reactive oxygen species (ROS). This change activates Src family kinases that phosphorylate PDGFR and thereby persistently trigger downstream signaling events such as P13K/Akt, which reduces the level of p53. Relaxing the p53 checkpoint potentiates the cell's ability to proliferate and survive, and facilitates the development of PVR.

Download his CV [PDF] for more information.

Education

Ph.D., Pharmacology, Peking Union Medical College, Beijing (2002)

Postgraduate Training

Ophthalmology Postdoctoral Fellowship, Schepens Eye Research Institute of Mass. Eye and Ear and Harvard Medical School (2002-2007)

Honors

2005: The Second Prize of Beijing Science and Technology Progress Award, Beijing Association for Science and Technology, Beijing, China

His Story

What is PVR?

Proliferative vitreoretinopathy, or PVR, is a vision-threatening complication that develops in 8–10% of patients who undergo retina-attachment surgery for rhegmatogenous retinal detachment (RRD) and 40–60% of patients with open-globe injury. It involves the formation of pathological fibrotic membranes (scarring) that detach the retina.

Development of PVR

PVR develops in patients who have retinal detachment or open-globe injuries. During the process, vitreous enhances cellular proliferation, survival, and extracellular matrix production of cells (e.g., retina pigment epithelial cells, glial cells) for the formation of the pathological fibrotic membranes. These membranes can detach the retina, and thereby, compromise an individual's ability to see.

Can PVR be Prevented?

Prevention of PVR is likely to emerge as we improve our understanding of how this blinding condition develops. Recent studies identified MDM2 SNP309 as associated with the risk of developing PVR and agents in the vitreous that promote pathological events that are responsible for formation and contraction of a PVR membrane.

Projects

Research Interests

  • Proliferative vitreoretinopathy (PVR)
  • Intraocular pathological angiogenesis

Platelet-Derived Growth Factors (PDGF) and PVR

Dr. Lei is investigating the mechanisms by which growth factors drive biochemical and cellular responses intrinsic to PVR. He plans to apply this information to the development of new therapeutic options for prevention of PVR.

Prevention of Pathological Intraocular Angiogenesis

VEGF plays a central role in angiogenesis, the process by which new blood vessels grow from pre-existing vasculature. Its receptor, VEGFR2, mediates almost all known VEGF-induced output, including neovascularization. Inhibition of VEGF-stimulated activation of VEGFR2 has become an important therapy for abnormal angiogenesis associated with proliferative diabetic retinopathy (PDR) and neovascular age-related macular degeneration (AMD). However, many patients who are not responsive to the anti-VEGF treatment. Dr. Lei is exploring novel therapeutic approaches to PDR and AMD.

Current Research Funding

2015-2018
 

National Institutes of Health/National Eye Institute: Principal Investigator
PDGF and PV
Dr. Lei is investigating the mechanism(s) by which growth factors drive biochemical and cellular responses intrinsic to PVR. He plans to apply this information to the development of new therapeutic options to prevent PVR.

Publications

Selected Publications

Dr. Lei has published more than 32 peer-reviewed articles. Below is a list of selected publications. View his publications on PubMed.

  1. Ma G., Duan Y., Huang X., Qian C., Chee Y., Mukai S., Cui J., Samad A., Matsubara J., Kazlauskas A., D’Amore P., Yan G., Lei H. Prevention of proliferative vitreoretinopathy by suppression of phosphatidylinositol 5-phosphate 4 kinases. Investigative Ophthalmology & Visual Science. 2016, 57(8): 3935-43.
  2. Duan Y., Ma G., Huang X., D’Amore P.A., Zhang F., Lei H. The CRISPR/Cas9-created MDM2 T309G enhances vitreous induced expression of MDM2 and proliferation and survival of cells. Journal of Biological Chemistry. 2016, 291(31): 16339-47.
  3. Lei H., Qian, C.X., Lei, J., Haddock, LJ, Mukai S, Kazlauskas A. RasGAP promotes autophagy and thereby suppresses platelet-derived growth factor receptor-mediated signaling events. Molecular & Cellular Biology. 2015, 15; 35 (10):1673-85.
  4. Lei H, Kazlauskas A. A reactive oxygen species-mediated, self-perpetuating loop persistently activates platelet-derived growth factor receptor α. Molecular & Cellular Biology. 2014; 34 (1) 110-22. PMID: 24190966
  5. Lei H, Rheaume MA, Cui J, Mukai S, Maberley D, Samad A, Matsubara J, Kazlauskas A. A novel function of p53: a gatekeeper of retinal detachment. American Journal of Pathology. 2012; 181: 866-74.

Patent

Antagonist Peptides to VEGF Receptor flt-1
Shou C, Lei H, Ping A, Wu J, Meng Ling, Liu X, inventors; Beijing Institute for Cancer Research, assignee. US patent 7,250,395. July 31, 2007.
Dr. Lei demonstrated that this novel peptide can suppress tumor growth and metastasis in mice.This invention shows promise as a novel treatment for angiogenic diseases.