Husain Lab Research Interests
The Husain Lab is currently focused on three key areas: (1) The crucial signaling pathways that initiate and transduce pancreatitis; (2) the factors that turn on pancreatic regeneration and recovery after pancreatic injury; and (3) the mechanisms underlying specific forms of drug-induced pancreatitis (DIP).
The crucial signaling pathways that initiate and transduce pancreatitis
Our early work demonstrated that abnormal acinar cell calcium signals play a crucial role in initiating and transducing acute pancreatitis. We showed for the first time that abnormally elevated calcium signals in the basolateral region of acinar cells are associated with pathologic intra-acinar protease activation, an early and critical event in the development of pancreatitis. This calcium signal is mediated by an endoplasmic reticulum (ER) calcium channel, the ryanodine receptor (RyR). We went on to examine mechanisms that regulate this pathologic RyR calcium release in the acinar cell and showed that increasing cAMP in acinar cells caused RyR opening, likely through RyR phosphorylation. We also found that the RyR was an important trigger for alcohol, a leading cause of pancreatitis. We further demonstrated that human acinar cells express functional RyRs which mediate acinar pathology.
Our studies on pathologic calcium signals progressed to determining potent calcium targets leading to pancreatic injury and pancreatitis. We discovered that the calcium-dependent serine, threonine phosphatase calcineurin (Cn) is a novel target of this pathological calcium signal. We used genetic and pharmacologic strategies to examine the role of Cn in clinically relevant experimental models of pancreatitis in vivo and specifically within the pancreatic acinar cell. We believe that this emerging and highly translationally relevant work will provide a basis for understanding the role of Cn in various forms of pancreatitis and will lay the framework for novel clinical trials that target pancreatitis using Cn inhibitors.
The factors that turn on pancreatic regeneration and recovery after pancreatic injury
In the hot pursuit of pancreatitis therapies, we hypothesized that a novel, alternate strategy to treating pancreatitis would be to examine the factors that turn on pancreatic regeneration and recovery in response to injury. Based on three key observations: (1) that valproic acid, a drug which is definitely associated with pancreatitis, is an inhibitor of an important class of epigenetic proteins the histone deacetylases (HDACs); (2) that HDACs mediate pancreas development; and (3) that elements of pancreas development are recapitulated during pancreatic recovery—we hypothesized that HDACs are crucial for activating the programs necessary for pancreatic recovery. We have thus far determined that HDACs appear to mediate the redifferentiation of intermediate regenerative structures, which are formed during the recovery process, back to mature pancreatic acinar cells. We are currently examining the nuclear HDAC complexes that appear to mediate this role in completing the recovery process. On a broader level, we are in the process of performing a large-scale characterization of the epigenomic and transcriptomic landscape during pancreatic recovery after injury. We believe these insights about new gene signatures will unravel novel discoveries that will help us devise treatments to counteract organ injury or boost recovery from injury.
The mechanisms underlying specific forms of drug-induced pancreatitis (DIP)
Drug-induced pancreatitis (DIP) is a leading etiology for pancreatitis in children. However, the mechanisms underlying DIP in the overwhelming majority of drug exposures is completely unknown. A leading culprit in DIP is the crucial cancer drug asparaginase. Using both clinical samples and experimental models, we have currently focused our efforts on deciphering the mechanisms by which asparaginase predisposes patients to pancreatitis. We anticipate that this work will help us devise novel therapies to prevent or mitigate asparaginase-associated pancreatitis and, on a broader level, will help elucidate how drugs can cause pancreatitis.
The crucial signaling pathways that initiate and transduce pancreatitis
Our early work demonstrated that abnormal acinar cell calcium signals play a crucial role in initiating and transducing acute pancreatitis. We showed for the first time that abnormally elevated calcium signals in the basolateral region of acinar cells are associated with pathologic intra-acinar protease activation, an early and critical event in the development of pancreatitis. This calcium signal is mediated by an endoplasmic reticulum (ER) calcium channel, the ryanodine receptor (RyR). We went on to examine mechanisms that regulate this pathologic RyR calcium release in the acinar cell and showed that increasing cAMP in acinar cells caused RyR opening, likely through RyR phosphorylation. We also found that the RyR was an important trigger for alcohol, a leading cause of pancreatitis. We further demonstrated that human acinar cells express functional RyRs which mediate acinar pathology.
Our studies on pathologic calcium signals progressed to determining potent calcium targets leading to pancreatic injury and pancreatitis. We discovered that the calcium-dependent serine, threonine phosphatase calcineurin (Cn) is a novel target of this pathological calcium signal. We used genetic and pharmacologic strategies to examine the role of Cn in clinically relevant experimental models of pancreatitis in vivo and specifically within the pancreatic acinar cell. We believe that this emerging and highly translationally relevant work will provide a basis for understanding the role of Cn in various forms of pancreatitis and will lay the framework for novel clinical trials that target pancreatitis using Cn inhibitors.
The factors that turn on pancreatic regeneration and recovery after pancreatic injury
In the hot pursuit of pancreatitis therapies, we hypothesized that a novel, alternate strategy to treating pancreatitis would be to examine the factors that turn on pancreatic regeneration and recovery in response to injury. Based on three key observations: (1) that valproic acid, a drug which is definitely associated with pancreatitis, is an inhibitor of an important class of epigenetic proteins the histone deacetylases (HDACs); (2) that HDACs mediate pancreas development; and (3) that elements of pancreas development are recapitulated during pancreatic recovery—we hypothesized that HDACs are crucial for activating the programs necessary for pancreatic recovery. We have thus far determined that HDACs appear to mediate the redifferentiation of intermediate regenerative structures, which are formed during the recovery process, back to mature pancreatic acinar cells. We are currently examining the nuclear HDAC complexes that appear to mediate this role in completing the recovery process. On a broader level, we are in the process of performing a large-scale characterization of the epigenomic and transcriptomic landscape during pancreatic recovery after injury. We believe these insights about new gene signatures will unravel novel discoveries that will help us devise treatments to counteract organ injury or boost recovery from injury.
The mechanisms underlying specific forms of drug-induced pancreatitis (DIP)
Drug-induced pancreatitis (DIP) is a leading etiology for pancreatitis in children. However, the mechanisms underlying DIP in the overwhelming majority of drug exposures is completely unknown. A leading culprit in DIP is the crucial cancer drug asparaginase. Using both clinical samples and experimental models, we have currently focused our efforts on deciphering the mechanisms by which asparaginase predisposes patients to pancreatitis. We anticipate that this work will help us devise novel therapies to prevent or mitigate asparaginase-associated pancreatitis and, on a broader level, will help elucidate how drugs can cause pancreatitis.