Alan Segal, MD

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Residency

Fellowship

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Biography:

Dr. Segal is an electrophysiologist and nephrologist who is studying the biophysical properties and physiological regulation of epithelial (e.g., kidney, airway) and vascular (e.g., smooth muscle, endothelium) ion channels.  He has been supported by a physician-scientist award from the NIH and by the National Kidney Foundation and Polycystic Kidney Research Foundation in addition to independent research grant (R01) support from the NIH.  His clinical interests address the regulation of blood pressure, particularly in those with cardiovascular and renal disease.  He is spearheading the Cerebro-Oculo-Reno Protection (CORP) component of the Cardiovascular Research Institute at UVM. Its goal is to reduce the incidence of brain, eye, and kidney disease caused by hypertension, diabetes, and vascular inflammation.

Major Research Interests:

Dr. Segal is elucidating the biophysiological role of ion channels in health and disease. Cystic fibrosis, among numerous other diseases, is attributable to an epithelial channelopathy and defective chloride ion transport.  Other examples include: Liddle’s syndrome (severe hypertension and altered renal sodium transport in the distal tubule) and several forms of Bartter’s syndrome (hypotension and altered renal sodium chloride transport in the loop of Henle).

Dr. Segal discovered and characterized novel potassium and mechanogated renal cation channels that are crucial for proximal tubular function and, when injured (i.e., in acute or chronic renal failure), can promote derangements in the regulation of extracellular volume and blood pressure. In collaborative work with Dr. Gary Desir at Yale, he has cloned and characterized a voltage-gated potassium (K) channel (hKCNA10) from human kidney that is found in the heart, blood vessels, glomerulus, and proximal tubule. Its role in hypertension is being explored vigorously.  Dysfunction of other voltage-gated K channels relevant to insulin resistance and cardiac arrhythmias has been identified.

Dr. Segal’s laboratory has extensive biomedical instrumentation needed for detection, control, and recording of electrophysiological signals from: 1) sheets of epithelia or cell monolayers, 2) large cells (e.g., Xenopus oocytes), 3) amphibian or mammalian cells (e.g., cardiomyocytes), and 4) a specific membrane containing one to a few hundred individual ion channels with the use of the single-channel patch clamp technique.

Anticipated CVRI collaboration focuses on bone marrow stem cells to reverse channelopathies and facilitate life-long maintenance of an “optimal blood pressure.” The latter is a goal of CORP because achieving it is likely to markedly reduce the incidence of cerebro-vascular, oculo-vascular, and reno-vascular injury to the brain, eye, and kidney, respectively. CORP plans to be involved in both the basic science and application in initial clinical trials of renalase, a recently discovered renal enzyme that blocks for formation of catecholamines in the periphery in human subjects.

Recent Grant Support

NIH/NIDDK
RO-1 DK 64325  ATP-Sensitive K Channels in Renal Proximal Tubule
PI: Segal, Alan S. 8/01/2003 – 5/31/2008

NIH/NIDDK (Yale Consortium)
RO-1 DK 48105  Structure and Function of Renal K Channels
PI: Desir, Gary V. 4/01/2002 – 3/31/2006

NKF Research Fellowship Regulation of Apical Ion Channels in Proximal Tubule
National Kidney Foundation Fellowship for Tobin Hoppes, M.D.
Mentor: Alan Segal    2004-2005; 2006-2007

Publications:

Segal A. 2004. Hyperkalemia and inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 351(23):2450-1.

Davids MR, Segal AS, Brunengraber H, Halperin ML. 2004. An unusual cause for ketoacidosis. QJM 97(6):365-76.

Hurwitz CG, Hu VY, Segal AS. 2002. A mechanogated nonselective cation channel in proximal tubule that is ATP sensitive. Am J Physiol Renal Physiol 283(1):F93-F104.

Segal AS, Hayslett JP, Desir GV. 2002. On the natriuretic effect of verapamil: inhibition of ENaC and transepithelial sodium transport. Am J Physiol Renal Physiol 283(4):F765-70.

Tian S, Liu W, Wu Y, Rafi H, Segal AS, Desir GV. 2002. Regulation of the voltage-gated K+ channel KCNA10 by KCNA4B, a novel beta-subunit. Am J Physiol Renal Physiol 283(1):F142-9.

Hurwitz CG, Segal AS. 2001. Application of pressure steps to mechanosensitive channels in membrane patches: a simple, economical, and fast system. Pflugers Arch 442(1):150-6.

Lang R, Lee G, Liu W, Tian S, Rafi H, Orias M, Segal AS, Desir GV. 2000. KCNA10: a novel ion channel functionally related to both voltage-gated potassium and CNG cation channels. Am J Physiol Renal Physiol 278(6):F1013-21.

Yao X, Liu W, Tian S, Rafi H, Segal AS, Desir GV. 2000. Close association of the N terminus of Kv1.3 with the pore region. J Biol Chem 275(15):10859-63.

Mauerer UR, Boulpaep EL, Segal AS. 1998. Properties of an inwardly rectifying ATP-sensitive K+ channel in the basolateral membrane of renal proximal tubule. J Gen Physiol 111(1):139-60.

Mauerer UR, Boulpaep EL, Segal AS. 1998. Regulation of an inwardly rectifying ATP-sensitive K+ channel in the basolateral membrane of renal proximal tubule. J Gen Physiol 111(1):161-80.

Yao X, Segal AS, Welling P, Zhang X, McNicholas CM, Engel D, Boulpaep EL, Desir GV. 1995. Primary structure and functional expression of a cGMP-gated potassium channel. Proc Natl Acad Sci U S A 92(25):11711-5.