Samir M. Parikh, M.D.
Assistant Professor of Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-280C
Boston, MA 02215
Office Phone: 617-667-5813
Office Fax: 617-667-2646
A.B. in Chemistry magna cum laude Harvard University, Cambridge MA M.D., Founder's Medal, Vanderbilt University School of Medicine, Nashville TN Internship, Internal Medicine, Beth Israel Deaconess Medical Center, Boston MA Residency, Internal Medicine, Beth Israel Deaconess Medical Center, Boston, MA Fellowship, Nephrology, Beth Israel Deaconess Medical Center, Boston, MA Instructor in Medicine, Harvard Medical School, Boston MA Assistant Professor of Medicine, Harvard Medical School, Boston MA
Research Interests: Inflammation, vascular leakage, mitochondria, sepsis, and kidney injury.
Basic Research - Disruption of the microvasculature in sepsis - The innate immune response defines the earliest stages of the host's response to a microbial invader. We have hypothesized that the subsequent microvascular disruption that arises from host-pathogen interactions is not only a critical bottleneck in the pathogenesis of this disease that can be objectively quantified through non-invasive means, but also the most proximate cause of shock and multi-organ dysfunction that culminates in the death of affected individuals despite the application of antibiotics and intensive supportive measures.
In 2006, we proposed that Angiopoietin-2, a secreted protein made by vascular endothelium, may be both a circulating marker as well as a mediator of sepsis-induced vascular leakage. Our initial findings have been independently validated and extended by groups worldwide. We have since defined the performance features of circulating Angiopoietin-2 as a diagnostic and prognostic marker in sepsis, we have identified key components of the molecular signaling apparatus within endothelial cells that enables Angiopoietin-2 to potentiate vascular inflammation and leakage, and we have also found strong evidence of this pathway's involvement in related syndromes of acute vascular leakage, including systemic anthrax. Current efforts in the laboratory are focused on identifying novel regulators of the Angiopoietin pathway and evaluating these in clinically relevant models of vascular disease.
Mitochondrial response to the septic milieu - Multi-organ dysfunction precedes death in sepsis, a top-ten cause of adult mortality in the United States. Affected organs include the heart, lungs, brain, liver, and kidneys. Acute kidney injury in sepsis is not only common, but also compounds the lethality of sepsis alone. Despite massive dysfunction of the kidneys, cell death within this organ is scant, raising an important and unexplained paradox.
We have proposed that sub-lethal injury arises in the tubular epithelium of the septic kidney. These cells are highly metabolically active, engaged in the constant movement of atomic ions and other solutes against strong electrochemical gradients. Using unbiased screens, small-animal imaging, and complementary approaches, we have observed consistent evidence suggesting the development of mitochondrial injury and dysfunction within this epithelium. PGC-1alpha, a regulator of mitochondrial biogenesis, is not only suppressed in the septic kidney, but its induction may be necessary for renal recovery from sepsis. Current efforts are focused on understanding how PGC-1alpha is regulated in the kidney, what downstream effectors are involved in the recovery process, and how our knowledge of this pathway can be exploited for clinical benefit.
New and Noteworthy Publications:
Tran M, Tam D, Bardia A, Bhasin M, Rowe GC, Kher A, Zsengeller ZK, Akhavan-Sharif MR, Khankin EV, Saintgeniez M, David S, Burstein D, Karumanchi SA, Stillman IE, Arany Z, Parikh SM. PGC-1? promotes recovery after acute kidney injury during systemic inflammation in mice. J Clin Invest. 2011 Oct 3; 121(I0)L 4003-14. PMID: 21881206. This study was the first in vivo examination of PGC-1alpha in the kidney and the first to propose its involvement in the recovery from sepsis-induced acute kidney injury
Ghosh CC, Mukherjee A, David S, Knaus US, Stearns-Kurosawa DJ, Kurosawa S, Parikh SM. Impaired Tie-2 signaling contributes to vascular leakage and lethality of systemic anthrax. Proc Natl Acad Sci USA. 2012. Jun 19; 109(25): 10024-9. PMID: 22665799. Systemic anthrax is uncommon, but deadly because its toxins induce vascular leakage throughout the body. This study used baboons and genetic mouse models to identify Angiopoietins and their receptor, Tie-2, as important novel contributors to this disease.
Xie Z, Ghosh CC, Patel R, Iwaki S, Gaskins D, Nelson C, Jones N, Greipp PR, Parikh SM*, Druey KM. Vascular hyperpermeability induces the symptoms of Clarkson disease (the systemic capillary leak syndrome). Blood. 2012. May 3;119(18):4321-32. PMID: 22411873. Systemic capillary leak syndrome is a rare, remitting-relapsing disorder that produces sudden hypotension and extravasation of blood fluid into the body's soft tissues. This study was the first to identify a humoral leak-promoting activity in the sera of patients that was only present during flares of the disease.
David S, Mukherjee A, Ghosh CC, Yano M, Khankin EV, Wenger JB, Karumanchi SA, Shapiro NI, Parikh SM. Angiopoietin-2 may contribute to multi-organ dysfunction and death in sepsis. Crit Care Med. 2012. Nov; 40(11): 3034-41. PMID 22890252. In 2006, our group proposed Angiopoietin-2 as a potential circulating marker and mediators of adverse outcomes in sepsis. The above work combined results from 270 subjects with suspected infection, from sepsis models applied to Angiopoietin-2 heterozygous mice, and from cellular models of septic vascular leak prevented by an antibody targeting Angiopoietin-2 to provide novel mechanistic evidence to support Angiopoietin-2 as a candidate disease mediator.