M. Amin Arnaout
- : 617-726-5663
Our laboratory is interested in elucidating the molecular basis of human disease and in using this information to guide development of new and safer therapies. We utilize state of the art technologies, including genetics, genomics, biochemistry, cell biology, structural and computational biology and animal models of disease. Current research activities in my laboratory address the following topics:
A. Cell-matrix interactions: Structure-activity relationships in integrins.
Cells exist in a highly dynamic extracellular milieu consisting of complex chemicals and mechanical stress signals to which cells must continuously adjust and in turn modulate. In metazoa, the task of integrating these mechanochemical cues across the plasma membrane is divalent-cation-dependent and is mediated by integrins. Integrins are normally expressed in a low affinity state, but rapidly and reversibly switch into high affinity by agonists. Ligands then bind, activate integrins and trigger classic "outside-in" signals that regulate every aspect of cell function. A major effort in our laboratory is to understand the structural basis of integrin activation and signaling in differentiated normal cells, tumor cells and stem cells using biochemical, structural and animal models. A potential outcome is identifying biologicals and small molecule antagonists to treat common diseases linked to integrin dysfunction including heart attacks, autoimmunity, stroke and cancer.
B. Developmental Biology – Cell fate determination of in the hematopoietic system
The hematopoietic system originates from a small population of self-renewing hematopoietic stem cells that differentiate into the various erythroid, myeloid, and B and T lymphoid lineages. The hematopoietic lineages tend to be specified in a stepwise process of binary decisions, dependent on particular genetic programs under control of transcription factors. The lineage-specifying and autoregulatory factors PU.1 and GATA1 form a master genetic switch that is responsible for determining the myeloid/lymphoid and erythroid lineages, respectively, commonly acting in concert with lineage-restricted factors such as SCL/TAL1 and CCAAT/enhancer binding protein α (C/EBPα). We have shown that ZBP-89 (Zfp148), which belongs to a novel class of GC-rich binding transcription factors, regulates the developmental fate of hemangioblasts, the precursors of hematopoietic and vascular stem cells at the embryonic stage. ZBP- 89 also regulates stress hematopoiesis in the adult bone marrow, revealed in experiments using conditional ZBP-89 knockout mice.
C. Autosomal Dominant Polycystic Kidney Disease
ADPKD is the most common monogenic disease in humans, caused by dysregulation in diameter of tubular structures including kidney tubules and blood vessels, leading chronically to loss of renal function or acutely to cerebral hemorrhage due to ruptured vascular aneurysms. We have generated a mouse KO of ADPKD and demonstrated that PKD1, one of the two defective genes, plays an important role in vascular development. We also showed that the other gene, PKD2, encodes a TRP-like calcium channel, which is stabilized by the product of PKD1. We have now identified a transcriptional modulator of tubulogenensis, TAZ, which appears to play a role in tubular cell fate decisions in the zebrafish pronephros.
D. Kidney Regeneration
Despite decades of research and advances in patient care, mortality rates for patients with acute kidney injury have not significantly decreased. The mammalian kidney possesses the inherent potential for regeneration and recovery of tubular function following acute injury, through recruitment and proliferation of surviving tubular epithelium. However, limitation in the number of surviving tubular cells commonly leads to progressive loss of renal function and fibrosis. The signaling pathways regulating tubular epithelial cell response to ischemic or toxic injury are incompletely understood. Stem cell antigen- 1 (Sca-1, also called Ly6a) is a glycerophosphatidylinositol (GPI)-anchored protein, commonly used as a marker for the identification and isolation of stem cell populations. We have shown that Sca-1 has a wider cell distribution in the adult kidney, where it plays a renoprotective role.
E. Engineering kidney assist Devices
Accumulation of excess fluid and toxic metabolites are invariant consequences of kidney failure. Over the long-term, kidney problems have significant repercussions on cardiovascular and other diseases. We are working with our bioengineering group towards development of microfluidic devices and methods of filtering a liquid solution that may find medical applications such as. mobile kidney augmentation devices.