Associate Professor of Systems Biology
Harvard Medical School
Jagesh V. Shah is an Associate Professor of Systems Biology at Harvard Medical School and Medicine at the Brigham and Women’s Hospital and the Director of the Laboratory for Quantitative Cell Biology. He received his PhD in Medical Engineering and Medical Physics from the Harvard-MIT Division of Health Sciences and Technology in 1999. He carried out post-doctoral work with Professors Don Cleveland and Lawrence Goldstein at the Ludwig and Howard Hughes Medical Institutes at UC San Diego.
Dr. Shah’s research interests are focused on developing a molecular and quantitative understanding of cellular measurement. How cells integrate external signaling via primary cilia and its relationship to polycystic kidney disease, how cells count chromosomes to prevent aneuploidy and how cells calculate the local chemical gradient during chemotaxis. His lab using a combination of quantitative microscopy methods and computational modeling to dissect how biochemical systems make these calculations.
Signaling and mechanisms governing Intraflagellar Transport:
How do cells build supramolecular structures such as cilia and flagella?
Cells have developed many internal structures to interact with the external environment. Cilia and flagella are remarkable structures composed of the cytoskeletal component tubulin and other structural and motor elements. They can provide force such as in sperm, for swimming, or lung epithelia, for clearing fluid. Recently new findings from human polycystic kidney disease (PKD) demonstrate the role of the cilium as a flow sensor. The mutation in many elements of this flow sensor results in the development of renal cysts. We are studying the many proteins that are involved in the building and maintenance of the cellular cilium. This process has been well-studied in the green algae dinoflagellate Chlamydomonas reinhardtii and has been termed Intraflagellar Transport or IFT. We are identifying the human IFT proteins and assessing their role in cilia assembly and maintenance. These proteins will also form the basis of identifying genetic mutations that may give rise to PKD and other human diseases.
Ciliary pathways regulating cystic kidney disease and situs determination:
How do cilia control the development of tissues for left-right determination and epithelial morphogenesis?
Polycystic kidney disease represents a significant burden of end-stage kidney outcomes and human morbidity. In its autosomal dominant form (ADPKD), nearly all cases are accounted for by mutations in PKD1 and PKD2, genes that encode for polycystin-1 and polycystin-2, respectively. Rarer, syndromic forms of cystic kidney disease, such as nephronophthisis (NPHP) or Bardet-Beidl syndrome, have been strongly associated with genes required for the assembly and maintenance of the primary cilium, a microtubule-based organelle. While polycystins are located, in part, in the primary cilium, how defects in the primary cilium or the polycystins themselves give rise to cystogenesis remains largely unknown. Moreover, many of these genes, including Pkd2, also disrupt early developmental patterning events such as situs determination. Previous work from our lab has identified molecular pathways that regulate ciliary assembly, length regulation and IFT trafficking. We are investigating these pathways and their overlap with polycystins and cystogenesis, providing a potential unifying framework for cystic kidneys in a variety of cystic kidney disease states.
Regulation and signaling in the Mitotic Checkpoint:
How do cells prevent chromosome loss?
Cell division is the key mechanism by which all organisms grow and propagate. An essential element of this process is the equal division of genetic material to each of the progeny cells. Aneuploidy, or state of having an incorrect number of chromosomes, is a hallmark of cancerous lesions and extrachromosomal birth defects. The equal segregation of chromosomes is ensured by the mitotic checkpoint. This checkpoint responds to biochemical and biophysical signals to identify when chromosomes have still not attached to the spindle. Unattached chromosomes produce a signal that alerts the cell not to segragate the chromosomes. The identity of this signal is still only poorly understood, as is how it is produced. We are attempting to decipher the biochemical and biophysical signaling network that underlies a functioning mitotic checkpoint and how, in aneuploid cells, this network may function poorly. Ultimately, a well-developed model of the mitotic checkpoint should provide novel biomarkers for cancer detection and shed light on possible molecular targets for cancer therapy.
Chemical and physical sensing in chemotactic cells
How do cells use chemical and physical cues to polarize and move in complex environments?
Chemotaxis is the measurement of local soluble chemical gradients and the influence on directional migration. We are interested in cell polarization and motility under 3D confinement that imposes different geometric and physical constraints in comparison to 2-D migration and may better mimic interstitial migration that leukocytes experience in vivo. This approach has already identified a cellular response to hydraulic resistance that biases cellular motion – so-called barotaxis. More recent work reveals a directional memory in chemotactic leukocytes that permits orientation in the absence of a gradient, based on a previous gradient. These previously undescribed phenomena may have a significant role in the directional migration of leukocytes. We use microfabrication methods to generate dynamic, quantitative environments where chemical and physical inputs can be modulated and high resolution imaging provides a view of cellular signaling.
RECENT PUBLICATIONS
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1. Czarnecki, P.G. et al. ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning. Nature communications 6, 6023 (2015).
2. Silva, B.A., Stambaugh, J.R., Yokomori, K., Shah, J.V. & Berns, M.W. DNA damage to a single chromosome end delays anaphase onset. J Biol Chem 289, 22771-84 (2014).
3. Prentice-Mott, H.V. et al. Biased migration of confined neutrophil-like cells in asymmetric hydraulic environments. Proc Natl Acad Sci U S A 110, 21006-11 (2013).
4. Manning, D.K. et al. Loss of the ciliary kinase Nek8 causes left-right asymmetry defects. Journal of the American Society of Nephrology : JASN 24, 100-12 (2013).
5. Gaglia, G., Guan, Y., Shah, J.V. & Lahav, G. Activation and control of p53 tetramerization in individual living cells. Proceedings of the National Academy of Sciences of the United States of America 110, 15497-501 (2013).
6. Shah, J.V. Many defects make a cyst. Cell Cycle 11, 16 (2012).
7. Kops, G.J. & Shah, J.V. Connecting up and clearing out: how kinetochore attachment silences the spindle assembly checkpoint. Chromosoma 121, 509-25 (2012).
8. Czarnecki, P.G. & Shah, J.V. The ciliary transition zone: from morphology and molecules to medicine. Trends in cell biology 22, 201-10 (2012).
9. Hagan, R.S. et al. p31(comet) acts to ensure timely spindle checkpoint silencing subsequent to kinetochore attachment. Molecular biology of the cell 22, 4236-46 (2011).
10. Besschetnova, T.Y. et al. Identification of signaling pathways regulating primary cilium length and flow-mediated adaptation. Current biology : CB 20, 182-7 (2010).
11. Ciliberto, A. & Shah, J.V. A quantitative systems view of the spindle assembly checkpoint. The EMBO journal 28, 2162-73 (2009).