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Search Results to Hemant Khanna PhD

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Lab Website

Additional Affiliations

Program in Cell Dynamics

Neurotherapeutics Institute


Dr. Hemant KhannaCILIA are unique cellular organelles that extend from the surface of the cell in the form of an antenna. They are generated and maintained by an elaborate process of vesicular protein trafficking, microtubule extension and resorption and stringently regulated activity of microtubule motor proteins. This process is called Intraflagellar Transport (IFT). Cilia are involved in regulating diverse developmental and adulthood signaling cascades, including sonic hedgehog signaling and Wnt signaling. Being nearly ubiquitous, dysfunction of cilia results in severe developmental disorders, including neurodegenerative diseases of the eye and brain.

Photoreceptors (rods and cones) are highly polarized neurons with a distinct inner segment and a photosensitive outer segment. To carry out visual signaling cascades, photoreceptors undergo immense but stringently regulated trafficking of proteins from the site of synthesis in the inner segment to the outer segment. The outer segments are considered an extension of primary or sensory cilia, which are near ubiquitous organelles formed by the extension of the plasma membrane in a post-mitotic cell. Slight perturbations in the cilia-dependent protein trafficking machinery result in severe photoreceptor degenerative disorders, such as Retinitis Pigmentosa and Leber congenital amaurosis.


Schematic of a rod photoreceptor cell.

This electron microscopy image of a zebrafish photoreceptor depicts the remarkable development of sensory cilium with outer segment discs. The cilium extends from the basal body, continues into a transition zone followed by axoneme extension into the outer segment. All outer segment components are synthesized in the inner segment and transported directionally to the outer segment via the cilium.

Our lab investigates the Molecular and Cell Biological basis of Neurodegenerative Diseases of the Eye, with special focus on those caused due to defects of ciliary function in the photoreceptors, the light-sensing neurons of the Retina. These diseases include Retinitis Pigmentosa (RP) and Leber congenital amaurosis (LCA) and are characterized by progressive loss of night and day vision in patients. Photoreceptors are polarized sensory neurons with a distinct inner segment (IS) and the photosensory outer segment (OS). The OS is a sensory (or primary) cilium, which contains membranous discs arranged in a coin-stack like fashion. These discs are periodically shed at the tip and are renewed at the base. Such phenomena require a high level of stringently regulated trafficking of membrane and protein components from IS to OS via a narrow bridge-like structure, called the transition zone (TZ). The unique and distinct protein composition of the ciliary OS membrane of photoreceptors is essential to maintain the polar nature of the photoreceptors. Consistently, any defects in the trafficking machinery of photoreceptors due to dysfunction of the cilia results in degeneration and blindness.

The TZ of photoreceptor cilium is implicated in regulating the sorting and trafficking of specific protein and other cargo components to the OS. We are interested in understanding the development, composition and function of the photoreceptor ciliary TZ in order to obtain mechanistic insights into the mode of regulated protein trafficking and maintenance of photoreceptor polarity. Our studies have identified three key ciliary proteins that are involved in photoreceptor ciliary protein: RPGR (retinitis pigmentosa GTPase regulator), RP2 (retinitis pigmentosa 2), and CEP290 (centrosomal protein of 290 kDa). These proteins not only modulate ciliary transport but are also mutated in various forms of human retinal degenerative diseases. Following three major projects are currently being carried out in our laboratory:

PROJECT I: Functional Analysis of RPGR: RPGR is a ciliary protein mutated in a majority of X-linked RP cases (>75%) and is one of the most common cause of RP in humans. This project focuses on investigating the role of the TZ-associated protein RPGR in photoreceptor cilia. Our recent studies have revealed that RPGR exists in multiple protein complexes in mammalian retina, such as with Nephronophthisis (NPHP)-associated proteins and IFT proteins. Moreover, RPGR acts as a guanine exchange factor (GEF) for the small GTPase RAB8A, which is involved in cilia formation and photoreceptor protein trafficking. Our studies are specifically aimed at (i) delineating the role of RPGR as a GEF in photoreceptors, (ii) the cargo that is specifically delivered by RPGR to the outer segment, and (iii) the effect of human disease mutations on the function of RPGR. We have developed zebrafish and mouse models of RPGR dysfunction, which represent the human disease condition. Our investigations have also led to a successful gene therapy study to ameliorate RPGR-associated disease in two canine models.

PROJECT II: RP2 in X-linked RP: The RP2 gene is mutated in 10-15% of X-linked RP cases. Previous studies indicate a role of RPGR in ciliary trafficking and maintenance. However, its precise role in photoreceptors is still unclear. Our lab utilizes cell culture and animal models to investigate the function of RP2 and pathology of associated disease.

PROJECT III: LCA due to CEP290 mutations: CEP290 is another ciliary protein involved in regulating cilia formation. Mutations in CEP290 are a frequent cause of LCA, a childhood blindness disorder. Our lab has identified a naturally occurring mouse mutant of Cep290. Additionally, we have shown that CEP290 interacts with several distinct ciliary proteins in the retina and is involved in regulating protein trafficking as well as protein degradation. This project focuses on delineating the role of CEP290 in regulating photoreceptor cilia formation and maintenance and understanding the pathogenesis of CEP290-associated retinal degenerative diseases.

Our approach includes:

Proteomics: We utilize yeast two-hybrid, co-immunoprecipitation & Mass Spectrometry analyses to identify components of macromolecular complexes of photoreceptor cilia. Our previous studies have successfully identified a number of potential RPGR- and CEP290 -interacting proteins, which are involved in photoreceptor development and function.

Animal and in vitro models: To study disease progression and pathogenesis, we are generating knock out and transgenic mouse lines representing the human disease phenotype. Our analysis includes assessment of age-dependent photoreceptor degeneration and examination of defects in protein trafficking in photoreceptors. We are also generating in vivo gene knockdown mouse models using Cre/loxp system or by subretinal injection of shRNA -encoding viral vectors. A major focus of the lab is also on utilizing zebrafish as a model to delineate the function of ciliary disease proteins and the effect of mutations on photoreceptor development and maintenance. We are also generating in vitro cell line models of knockdown by using shRNA technology in neuronal as well as non-neuronal cell lines.


Injection of anti-sense morpholino (rpgr-MO) into zebrafish embryos

Injection of anti-sense morpholino (rpgr-MO) into aebrafish embryos result in developmental disorder, including shortened body axis and edema at 4 dpf.  Uninjected wild-type (WT) and embryo injected with the 5 base mismatch (Mm) control (rpgr-Mm)are also shown.  Arrows in the rpgr-MO panel depict the different morphological phenotypes observed in the defective embryos (left_) panels; hydrocephaly and kinked tail; right panel; edma).  Source:  Ghosh et al., Hum Mol Genet, 2010.


Lab Personnel

Linjing Li, PhD-Postdoctoral Fellow

K Nageswara Rao, PhD-Postdoctoral Fellow

Balaji Subramanian, PhD-Postdoctoral Fellow

Wei Zhang, PhD-Postdoctoral Fellow

Manisha Anand, Research Associate I

Post Docs

This position involves research projects, which focus on understanding the development and function of neuronal cilia, specifically photoreceptor cilia and development of therapeutic strategies for associated disorders. The work entails the use of bacterial, cell culture and animal models (mice and zebrafish). Experience in molecular biology and protein biochemistry are a requirement for this position. Prior experience of in vivo injections in mice and zebrafish is desirable.  Interested candidates should send their resume and a short statement of interest to: Manisha Anand (manisha.anand@umassmed.edu).

One or more keywords matched the following items that are connected to Khanna, Hemant

Item TypeName
Academic Article Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.
Academic Article CSPP is a ciliary protein interacting with Nephrocystin 8 and required for cilia formation.
Academic Article Interaction of ciliary disease protein retinitis pigmentosa GTPase regulator with nephronophthisis-associated proteins in mammalian retinas.
Academic Article Accumulation of the Raf-1 kinase inhibitory protein (Rkip) is associated with Cep290-mediated photoreceptor degeneration in ciliopathies.
Academic Article Ciliary signaling cascades in photoreceptors.
Academic Article Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons.
Academic Article CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease.
Academic Article Human retinopathy-associated ciliary protein retinitis pigmentosa GTPase regulator mediates cilia-dependent vertebrate development.
Academic Article RPGR-containing protein complexes in syndromic and non-syndromic retinal degeneration due to ciliary dysfunction.
Academic Article Multiprotein complexes of Retinitis Pigmentosa GTPase regulator (RPGR), a ciliary protein mutated in X-linked Retinitis Pigmentosa (XLRP).
Academic Article Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration.
Academic Article The retinitis pigmentosa protein RP2 interacts with polycystin 2 and regulates cilia-mediated vertebrate development.
Academic Article Expression and localization of the ciliary disease protein retinitis pigmentosa GTPase regulator in mammalian kidney.
Academic Article TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein.
Academic Article Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis.
Academic Article OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome.
Academic Article Ciliary transition zone (TZ) proteins RPGR and CEP290: role in photoreceptor cilia and degenerative diseases.
Academic Article Retina ciliopathies: from genes to mechanisms and treatment.
Concept Cilia
Concept Photoreceptor Connecting Cilium
Academic Article Cilia in photoreceptors.
Academic Article Ablation of retinal ciliopathy protein RPGR results in altered photoreceptor ciliary composition.
Academic Article Photoreceptor Sensory Cilium: Traversing the Ciliary Gate.
Academic Article Loss of retinitis pigmentosa 2 (RP2) protein affects cone photoreceptor sensory cilium elongation in mice.
Academic Article Tackling Primary Cilia Dysfunction in Photoreceptor Degenerative Diseases of the Eye.
Academic Article Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models.

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