Micheala A. Aldred Ph.D.

Associate Staff

  • Genomic Medicine Institute
  • Lerner Research Institute
  • 9500 Euclid Avenue
  • Cleveland, Ohio 44195
  • aldredm@ccf.org
  • Phone: (216) 445-4336
  • Fax: (216) 636-0009

Our work focuses on the genetics of pulmonary arterial hypertension (PAH), a serious lung vascular disorder. A subset of PAH cases are caused by germline mutations in genes of the bone morphogenetic protein (BMP) pathway, primarily BMPR2, but also SMAD9, ALK1 and endoglin. However, most cases are sporadic and the cause it unknown.  Our hypothesis is that somatic genetic changes, which are not inherited and occur only in the lung, contribute to the pathogenesis of PAH.  In collaboration with researchers at the Cleveland Clinic and elsewhere in the US, we have identified frequent chromosomal abnormalities in endothelial cells isolated from the lungs of patients with PAH.  We are now characterizing the functional changes associated with these abnormalities. We are also profiling additional genetic and epigenetic changes that may occur in PAH lungs.  A second project is to understand the role of microRNAs, small RNA molecules that regulate gene networks. A subset of microRNAs are regulated by the BMP pathway and we have shown that mutations in patients with familial PAH lead to loss of the pathway.  We are also studying the role of circulating endothelial progenitor cells (EPCs). In work funded by the American Heart Association, we are examining whether the characteristics of EPCs correlate with gene mutation status and also how their gene expression profiles differ from EPCs from control subjects. The long-term goal of these studies is to identify early markers of PAH and pathways that might be targeted by new treatments.

In other words ...

Pulmonary arterial hypertension (PAH), is a life-threatening condition affecting the lungs and heart.  Changes in the blood vessels of the lung lead to narrowing of the lumen, the space where blood flows, meaning that the pressure needed to pump blood through the lungs increases.  This increased pressure in turn puts strain on the right ventricle of the heart.  Our research examines the genetic changes that contribute to PAH.  A small proportion of PAH cases are due to inherited genetic changes, but most are sporadic and have no known cause.  We are studying the effects of these inherited genetic changes in families with PAH.  In the sporadic cases, we are using new approaches to test whether there are genetic alterations occurring just in the lung, which might contribute to development of PAH.  Our long-term goal is to identify new treatments that directly target these genetics changes and could potentially prevent the onset of disease in people who are at high risk of developing PAH.

  • Sirena Meade M.S.
  • Senior Research Technologist
  • Location:NE5-251
  • Phone:(216) 444-0030
  • meades@ccf.org
  • Amna Musharraf Ph.D.
  • Postdoctoral Fellow
  • Location:NE5-251
  • Phone:(216) 444-0030
  • mushara@ccf.org
  • Tammy Sadler M.S.
  • Lead Research Technologist
  • Location:NE5-251
  • Phone:(216) 444-0030
  • sadlert@ccf.org

Federici C, Drake KM, Rigelsky CM, McNelly LN, Meade SL, Comhair SA, Erzurum SC, Aldred MA (2015). Increased mutagen sensitivity and DNA damage in pulmonary arterial hypertension. Am J Respir Crit Care Med 192: 219-228. PubMed

Drake KM, Comhair SA, Erzurum SC, Tuder RM, Aldred MA (2015). Endothelial chromosome 13 deletion in congenital heart disease-associated pulmonary arterial hypertension dysregulates SMAD9 signaling. Am J Respir Crit Care Med 191: 850-854. PubMed

Long L, Ormiston ML, Yang X, Southwood M, Graf S, Machado RD, Mueller M, Kinzel B, Yung LM, Wilkinson JM, Moore SD, Drake KM, Aldred MA, Yu PB, Upton PD, Morrell NW (2015). Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med 21: 777-785. PubMed

Machado RD, Southgate L, Eichstaedt CA, Aldred MA, Austin ED, Best DH, Chung WK, Benjamin N, Elliott CG, Eyries M, Fischer C, Graf S, Hinderhofer K, Humbert M, Keiles SB, Loyd JE, Morrell NW, Newman JH, Soubrier F, Trembath RC, Viales RR, Grunig E (2015). Pulmonary Arterial Hypertension: a current perspective on established and emerging molecular genetic defects. Hum Mutat 36: 1113-1127. PubMed

Drake KM, Dunmore BJ, McNelly LN, Morrell NW, Aldred MA (2013). Correction of nonsense BMPR2 and SMAD9 mutations by Ataluren in Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 49:403-409. PubMed

Drake KM, Zygmunt D, Mavrakis L, Harbor P, Wang L, Comhair SA, Erzurum SC, Aldred MA (2011). Altered microRNA processing in heritable Pulmonary Arterial Hypertension: an important role for Smad-8. Am J Respir Crit Care Med 184:1400-1408. PubMed

Aldred MA, Comhair SA, Varella-Garcia M, Asosingh K, Xu W, Noon GP, Thistlethwaite PA, Tuder RM, Erzurum SC, Geraci MW and Coldren CD (2010). Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 182:1153-1160. PubMed