Kameran Lashkari, M.D.

Harvard Medical School

Assistant Professor of Ophthalmology, Part-Time

Schepens Eye Research Institute of Massachusetts Eye and Ear

Assistant Scientist

Research Summary

Center/Research Area Affiliations

Biography

Dr. Lashkari is investigating novel biomarkers and their impact on the pathophysiology of ocular disease, including AMD, proliferative diabetic retinopathy, and diabetic macular edema (DME). In AMD, he has identified distinct biomarkers associated with intermediate dry, advanced dry (geographic atrophy), and wet AMD. Several of these biomarkers are also potential therapeutic targets in AMD. Dr. Lashkari has identified other therapeutic targets in the super-VEGF family that are particularly helpful in cases of wet AMD that are resistant to anti-VEGF-A monotherapy. In the area of diabetic retinopathy and DME, Dr. Lashkari is also developing biomarkers that may be involved in alterations in tissue permeability and angiogenesis. To this end, Dr. Lashkari has an established long-term collaboration with various local and international pharmaceutical companies.

Dr. Lashkari also investigates the application of retinal progenitor cells (RPC) in tissue replacement and cell-based neurotrophic therapy. He has shown that transplanted RPCs expressing various factors can prevent development of optic nerve damage in experimental glaucoma. This work can be applied to glaucoma, the optic nerve, and retina degeneration.

Additionally, Dr. Lashkari has studied the role of growth factors and down-streak regulators in retinal would healing and RPE cell biology. These include studies on the role of hepatocyte growth factor in retinal laser injury.

Download his CV or biosketch [PDF] for more information.

Education

M.D., New York Medical College (1985)

Postgraduate Training

Internal Medicine Residency, St. Vincent’s Hospital and Medical Center (1986-1988)
Chief Resident, St. Vincent’s Hospital and Medical Center (1988-1989)
Medical Retina and Research Fellowship, Schepens Eye Research Institute of Mass. Eye and Ear (1989-1990)
Ophthalmology Residency, University of Missouri Eye Foundation of Kansas City, (1990-1992)
Chief Resident, University of Missouri Eye Foundation of Kansas City (1992-1993)

Honors

2007-2014: Stone Scholar Endowment Award, Schepens Eye Research Institute of Mass. Eye and Ear (renewed)
2002-2007: Stone Scholar Endowment Award
1999-2002 and 1989-1999: Clinical Investigator Award, Schepens Eye Research Institute of Mass. Eye and Ear

His Story

Retinal Progenitor Cells for Glaucoma and Retinal Degeneration

Persistent fetal vasculature (PFV) is described as a phenomenon of failed regression of the vascular bed in the eye. In general, the hyaloid vascular system (HVS) nourishes the developing lens and regresses late in human fetal development. In PFV, the remnants of the HVS, together with fibroblasts and occasional pigmented cells, form a fibrovascular membrane that grows behind the lens and can incorporate retinal elements. These membranes are dissected and removed from the eye without disturbing the underlying retinal tissue.

Novel findings from Dr. Lashkari’s laboratory indicate that the fibrovascular membranes from PFV patients are replete with retinal progenitor cells that form clusters of nestin positive cells within a local niche. The laboratory has successfully isolated and characterized these progenitor cells (herein, called PFV cells). The researchers have found that PVF cells are programmed to differentiate solely into a neuronal/retinal lineage, with predilection to develop into retinal ganglion cells (that form the optic nerve).

In support of this contention, PFV cells transplanted into the vitreous of C57BL/6 mice differentiate into retinal neurons. Additionally, these cells have been maintained in culture for an extended period of time and have continued their progenitor phenotype with no evidence of malignant transformation. This novel finding may have an important impact on regenerative approaches to future management of advanced glaucoma, in which there is selective loss of retinal ganglion cells resulting in optic atrophy and in retinal degeneration, in which there is loss of outer retinal layers. He is characterizing both in vitro and in vivo properties of PFV cells before and after xenotransplantation to replace the lost retinal and ganglion cells, including their survival, connectivity and gain of visual function.

Pathogenesis of Advanced Retinopathy of Prematurity

Advanced retinopathy of prematurity (ROP) is the leading cause of childhood blindness. It is characterized by intense retinal neovascularization—resulting in traction retinal detachment and the formation of fibrovascular membranes that lead to total retinal detachment. Clinical evidence shows that the process of retinal neovascularization occurs on the border between vascularized and peripheral, avascular retina. The latter is the putative source for the release of VEGF, which is closely involved with this process. It is not clear why advanced ROP develops in some patients, as this intense process of angiogenesis leading to advanced ROP has not been replicated in an animal model.

Dr. Lashkari’s goal is to identify factors that participate in advanced ROP, using tissue collected from patients with this condition. Much of the work is focused on cellular and biochemical processes that contribute to the formation of retinal neovascular membranes (RNM). He has shown that RNM is comprised of two major compartments—a retinal neural/glial compartment and a vascular compartment. The neural compartment is comprised of adult and progenitor cells that would normally participate in development of the adult retina. RNMs contain nestin-positive cells that form neurospheres in vitro, and that can be induced to differentiate into a mature neuronal/retinal lineage in preference to a glial lineage, as shown by photoreceptor and bipolar cell markers. Fluorescent-tagged or GFP-expressing progenitor cells, introduced by viral vectors injected into the subretinal space of SCID mice, survive and differentiate into morphologically mature neuronal and retina-like elements.

Researchers in Dr. Lashkari’s laboratory are currently characterizing the expression of several tyrosine kinase receptors in the RNMs, including VEFGR-2 and hMet/ HGFR, as they have found that these markers are expressed very early in the lineage. They have also studied the vascular compartment of RNMs by double-fluorescence imaging. They have shown that there are distinct endothelial cell compartments within the RNM, suggesting that there is a significant contribution from endothelial progenitor cells. These include (1) CD31+/VE-Cadherin+/CD34-/ CD133- endothelial cells associated with mature blood vessels, (2) CD34+/Tal-1+/CD31- endothelial cells representing early, immature blood vessels, and (3) individual cells expressing CD34+/CD133+/GFAP, probably representing endothelial precursors within the stroma of these membranes.

These findings suggest that the RNM is a very complex tissue that contains many different cellular elements. Furthermore, they are analyzing the subretinal fluid (SRF) compartment in eyes with advanced ROP. They have postulated that, as the retina is the target of intense retinal angiogenesis, the SRF may be a good source for analysis of putative pro-angiogenic agents. They have previously shown that VEGF levels were highly elevated, in excess of HGF on a weight basis, in SRF from stage 4 ROP and equally elevated in stage 5 ROP. We have further sizefractionated SRF and subjected these fractions to an in vitro angiogenesis assay using capillary endothelial cells placed in three-dimensional fibrin clots. This procedure allows us to determine which fraction exhibits the most robust pro-angiogenic activity. We are currently performing proteomic techniques, including 2-D gel analysis with mass spectroscopy and luminex analysis on selected albumin and globulin-depleted SRF fractions.

Hepatocyte Growth Factor and RPE Cell Biology in Response to Wound Healing and Laser Injury

The human eye is extremely vulnerable to direct laser injury, and maintaining good vision is an important determinant in success of military operations, and even survival of military personnel in theatre. Laser injury resulting from its use as a weapon or through inadvertent retinal exposure (range finder, etc.) can immediately and potentially severely impact vision. There is increasing use of the Nd- YAG laser in military operations, resulting in an increased risk of potentially blinding exposure by military personnel. As a result, there has been congressional appeal and military interest to develop a treatment modality that could be applied to immediately counteract acute retinal laser injury in the battlefield before debilitating injury results.

Injury from laser irradiation comprises a partial disruption of the retinal pigment epithelium (RPE), remodeling of the monolayer into more motile cell types, formation of scar tissue, and eventual loss of vision. The hepatocyte growth factor (HGF) and its receptor (HGFR) have been implicated in wound healing responses.

As part of our current department of defense project, we are studying the role of HGF and its receptor in retinal / RPE injury and wound healing in a mouse model of laser injury. Dr. Lashkari’s current results indicate that HGF itself becomes upregulated following laser injury and activates its receptor, HGFR. Anatomically, this process is closely correlated with enhanced RPE motility.

In the current study, he hypothesizes that HGFR activation is closely associated with RPE responses to laser injury and abrogation of HGFR activity can taper RPE motility and the detrimental wound healing response that ensues. We will employ a transgenic mouse approach to directly manipulate the activity of HGFR following Nd-YAG laser-induced retinal injury. He expects that abrogation of HGFR activity will result in decreased wound healing responses and reduced disruption of retinal anatomy following laser injury. This project directly addresses the mechanisms of retinal injury and wound healing caused by Nd-YAG lasers in combat and non-combat military conditions. Dr. Lashkari plans to design selective inhibitors for HGFR in order to taper wound healing responses.

Publications

H-index

17 (Google Scholar, as of May 2017)

Selected Publications

Dr. Lashkari has published more than 40 peer-reviewed articles. Below is a list of selected publications. View his publications on PubMed or Google Scholar.

  1. Ma J, Guo C, Guo C, Sun Y, Liao T, Beattie U, Lopez FJ, Chen DF, Lashkari K. Transplantation of human neural progenitor cells expressing IGF-1 enhances retinal ganglion cell survival. PLoS ONE 2015;10(4):e0125695.
  2. Kovacs K, Marra KV, Yu G, Wagley S, Ma J, Teague GC, Nandakumar N, Lashkari K, Arroyo JG. Angiogenic and inflammatory vitreous biomarkers associated with increasing levels of retinal ischemia. Invest Ophthalmol Vis Sci. 2015;56(11):6523-30.
  3. Ma J, Mehta M, Lam G, Cyr D, Ng TF, Hirose T, Tawansy KA, Taylor AW, Lashkari K. Influence of subretinal fluid in advanced stage retinopathy of prematurity on proangiogenic response and cell proliferation. Mol. Vis. 2014; (20):881-893.
  4. Ma J, Lopez FJ, Adamson P, Kurali E, Lashkari K. Blockage of PI3K/mTOR pathways inhibits laser-induced choroidal neovascularization and improves outcomes relative to VEGF-A suppression alone. Invest Ophthalmol Vis Sci. 2016;57(6):3138-3144
  5. Kasaoka M, Ma J, Lashkari K. c-Met modulates RPE migratory response to laser-induced retinal injury. PLoS One. 2012. 7(7) e40771.

Patents

For a complete list of Dr. Lashkari’s patents, download his CV [PDF].

Electro-Optic Binocular Indirect Ophthalmoscope
Harooni M. & Lashkari K. U.S. Patent No. 5,841,509
This invention describes a system for imaging in the near infrared (NIR) that obviates any need for pupillary dilation. It entails designs for an indirect binocular ophthalmoscope that can image the retina in real time in NIR. It is particularly suited for pediatric exams and triaging patients without the need for pupillary dilation. This invention has military applications, as a simpler version of the ophthalmoscope can be designed to be use by medics in real time.

Electro-Optic Binocular Indirect Ophthalmoscope for Stereoscopic Observation of Retina
Lashkari K & Harooni M. U.S. Patent No. 6,089,716
Continuation of prior art (see above).

Electro-Optic Binocular Indirect Ophthalmoscope
Lashkari K & Harooni M. U.S. Patent No. 6,350,031
Continuation of prior art (see above).

Laboratory

Current Members of Dr. Kameran Lashkari’s Laboratory

Jie Ma, PhD
Gianna Teague

Alumni

More than 14 trainees have worked in Dr. Lashkari’s laboratory. To view the complete list of alumni, download his CV [PDF].