Biography

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The focus of my current research is to understand mechanisms of cellular signaling at the level of the primary cilia, and its relevance to human health and disease. My interests in ciliary signaling began when I was a graduate student at Brandeis with Dr. Piali Sengupta. I utilized C. elegans to study the mechanisms that determine the distinctive ciliary morphology of their sensory neurons. In my postdoctoral years in Dr. Peter Jackson’s lab at Genentech, using high-confidence proteomic approaches, I discovered the role of tubby family protein TULP3 in trafficking of GPCRs to cilia by coupling to the ciliary intraflagellar complex-A (IFT-A). I also identified an orphan GPCR, GPR161 that acts as a negative regulator of Sonic hedgehog (Shh) signaling during neural tube development via cAMP signaling by dynamically localizing to cilia.

My laboratory has made numerous contributions to the field of ciliary trafficking and signaling. We have now established tubby family proteins, TULP3 and Tubby as critical determinants for trafficking of almost all known rhodopsin family GPCRs to cilia. By extending the repertoire of Tulp3-dependent ciliary cargoes to include (a) Polycystins and Fibrocystin, proteins implicated in polycystic kidney disease (PKD), and (b) ARL13B, an atypical small GTPase linked to renal cystogenesis and trafficking lipidated cargoes, we have identified the predominant mechanism for trafficking of multiple types of membrane proteins to cilia. We have also demonstrated that embryonic stage nephron-specific Tulp3 knockout mice develop cystic kidneys, while retaining intact cilia. TULP3 and the brain-specific Tubby have now been established as the central players for trafficking multiple membrane-bound cargoes into mammalian cilia.

In parallel, we have been in the forefront of understanding the complex role of primary cilium-generated signaling, particularly that of negative regulation by GPR161, in the Shh pathway. We have also recently discovered that the MYND domain protein ANKMY2 serves as a critical negative regulator of Shh pathway during neural tube development by trafficking multiple adenylyl cyclases to cilia. Our discovery of GPR161 as a moderately strong repressor of the Shh pathway, and our ability to study cilium-generated signaling have unraveled new phenotypes arising from derepression of Shh signaling in multiple developmental paradigms. In collaboration with Dr. Richard Finnell, we have detected GPR161 mutations in patients suffering from neural tube defects (Hum Mol Gen, 2018, 28, 200-208). Others have linked germ line GPR161 mutations in human patients with predisposition to Shh-subtype medulloblastoma at rates similar to loss of Shh receptor PTCH1 (J Clin Oncol 2020, 38, 43-50).

Overall, our expertise in Shh signaling and its regulation by cilia, our demonstrated strengths in utilizing a multi-pronged approach including proteomics, cell biology, and reverse genetics to discover novel Shh pathway regulators, including the discovery of the Tulp3-Gpr161-Ankmy2 axis, and further engineering of conditional knock out and knock in alleles targeting these factors, uniquely position us to determine the role of basal suppression of Shh signaling in these diverse processes. Finally, the collaborative nature of research and the strong focus on translational biomedical research at UT Southwestern is instrumental for studying these diverse developmental paradigms aiming at understanding the role of primary cilia in development and disease.

Education

Undergraduate
(1998), Medicine
Medical School
Banaras Hindu University (2002), Medicine
Graduate School
Brandeis University (2008), Biology

Research Interest

  • Cilia organized signaling pathways
  • Cilia specific signals in PKD
  • Ciliary regulation of limb and skeletal development  
  • Ciliary signaling in neural tube development and disease
  • Cilium-centrosome complex in Shh-medulloblastoma pathogenesis

Publications

Featured Publications LegendFeatured Publications

Honors & Awards

  • Alex Lemonade Stand Foundation A-grant awardee
    (2017-2021)
  • W.W. Caruth, Jr. Scholar in Biomedical Research
    Endowed scholar, UT Southwestern (2013)
  • CPRIT Scholar in Cancer Research
    (2012-2018)

Professional Associations/Affiliations

  • Member, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center. (2013)
  • American Society for Cell Biology. (2005)